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==2x36 - Structure of the proteolytic domain of the <scene name='86/868177/Structure_hmlon_protease/1'>Human Mitochondrial Lon protease</scene>==<br />
<StructureSection load='2x36' size='340' side='right' caption='Structure of the Human Mitochondrial Lon protease' scene=''><br />
<br />
<br />
== Generalities ==<br />
<br />
<p align="justify">'''2x36''' is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. This domain belongs to the [https://en.wikipedia.org/wiki/Lon_protease_family Lon protease family]. <br />
<br><br />
[https://en.wikipedia.org/wiki/Mitochondrion Mitochondrial] Lon [https://en.wikipedia.org/wiki/Protease protease] is an '''ATP-dependent serine protease''' involved '''in the selective degradation of abnormal proteins'''. [https://en.wikipedia.org/wiki/LONP1 LONP1] situated on chromosome 19 is the nuclear gene encoding mitochondrial Lon protein. The single species of [https://en.wikipedia.org/wiki/Messenger_RNA mRNA] of this protein is found in the mitochondrial matrix. This protein from human tissues has a molecular mass of 100 [https://en.wikipedia.org/wiki/Dalton_(unit) kDA].</p> The proteolytic domain of Lon is the center of the Lon protease activity. <br />
<br><br />
== Function ==<br />
<br />
<p align="justify">The mitochondrial Lon protease is an important regulator of mitochondrial [https://en.wikipedia.org/wiki/Metabolism metabolism] including the maintenance and repair of mitochondrial [https://en.wikipedia.org/wiki/DNA DNA] thanks to its proteolytic domain. This protein is also essential for homeostasis of mitochondria, and by regulating some regulatory proteins which have a short life or damaged proteins. <br />
<br><br />
<br><br />
Lon protease has three main roles<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. <br />
This protein is able to do a '''[https://en.wikipedia.org/wiki/Proteolysis proteolytic] digestion''' of oxidized proteins which allows the renewal of essential mitochondrial enzymes such as [https://en.wikipedia.org/wiki/Aconitase aconitase] or [https://en.wikipedia.org/wiki/TFAM Mitochondrial transcription factor A].<br />
Lon protease is involved in [https://en.wikipedia.org/wiki/Mitochondrial_DNA mtDNA] [https://en.wikipedia.org/wiki/DNA_replication replication] and [https://en.wikipedia.org/w/index.php?title=Mitogenesis&redirect=no mitogenesis] by being a '''mitochondrial [https://en.wikipedia.org/wiki/DNA-binding_protein DNA-bing protein]'''. Human Lon and mtDNA associate at the level of their at least 4 contiguous [https://en.wikipedia.org/wiki/Guanine guanine] sequence and form a [https://en.wikipedia.org/wiki/G-quadruplex G-quadruplex]<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. This G-rich region is the control region for mtDNA replication and transcription<ref>Lu, Bin. “Mitochondrial Lon Protease and Cancer.” Advances in Experimental Medicine and Biology 1038 (2017): 173–82. https://doi.org/10.1007/978-981-10-6674-0_12.</ref>. <br />
<br><br />
Mitochondrial Lon protease interacts with '''[https://en.wikipedia.org/wiki/Chaperone_(protein) protein chaperone]''', notably [https://en.wikipedia.org/wiki/Chaperonin HSP60]-[https://en.wikipedia.org/wiki/Hsp70 Hsp70] complex to protect cell from apoptosis under environmental stress<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>.<br />
<br><br />
The mitochondrial Lon protease is essentially found in the cytoplasmic of mitochondria because [https://en.wikipedia.org/wiki/Amino_acid amino-acid] has a potential mitochondrial targetting presequences<ref>García-Nafría, Javier, Gabriela Ondrovičová, Elena Blagova, Vladimir M Levdikov, Jacob A Bauer, Carolyn K Suzuki, Eva Kutejová, Anthony J Wilkinson, and Keith S Wilson. “Structure of the Catalytic Domain of the Human Mitochondrial Lon Protease: Proposed Relation of Oligomer Formation and Activity.” Protein Science : A Publication of the Protein Society 19, no. 5 (May 2010): 987–99. https://doi.org/10.1002/pro.376.</ref>.<br />
<br><br />
Lon Human protease alternates between cycles of '''being bound to the mitochondrial genome''' and '''being free into the mitochondrial cytoplasm''' thanks to the proteolytic domain where it can degrade abnormal proteins coming from damaged proteins, errors in the synthesis, or [https://en.wikipedia.org/wiki/Protein_folding misfolded] of multimeric proteins. Its inactive conformation prevents uncontrolled proteolysis by the proteolytic domain. <br />
To achieve proteolytic cleavage, the Lon protein has to form a hexamer. <br />
Lon protease has also a role in mtDNA quality control by permits oxidative mitochondrial DNA damage. Sensitivities of H2O2-induced mtDNA damage depend on the proportion of LON<ref>Lu, Bin. “Mitochondrial Lon Protease and Cancer.” Advances in Experimental Medicine and Biology 1038 (2017): 173–82. https://doi.org/10.1007/978-981-10-6674-0_12.</ref>. <br />
Other ATP-dependent proteases are found in eukaryotic cells and organelles like [https://en.wikipedia.org/wiki/Proteasome_endopeptidase_complex 26S protease] which uses [https://en.wikipedia.org/wiki/ATP_hydrolysis ATP hydrolysis] for conjugation or ubiquitin for example.</p><br />
<br><br />
<br />
== General structure ==<br />
<br />
<p align="justify">Lon proteins are grouped into two families, '''LonA''' and '''LonB'''. The human protein LonP1 is part of the LonA proteins <ref>« The N-terminal domain plays a crucial role in the structure of a full-length human mitochondrial Lon protease | Scientific Reports ». Consulté le 13 janvier 2021. https://www.nature.com/articles/srep33631.<br />
</ref>. This protein has three isoforms obtained by [https://en.wikipedia.org/wiki/Alternative_splicing alternative splicing] of the portion of DNA coding for this protein <ref>He, Lihong, Dongyang Luo, Fan Yang, Chunhao Li, Xuegong Zhang, Haiteng Deng, et Jing-Ren Zhang. « Multiple domains of bacterial and human Lon proteases define substrate selectivity ». Emerging Microbes & Infections 7 (17 août 2018). https://doi.org/10.1038/s41426-018-0148-4.<br />
</ref>.<br />
Globally there is a great diversity of Lon proteins, but they are all organized in an oligomeric ring structure, mostly hexameric structure with identical subunits.<br />
Lon proteins are therefore an hexameric chambered [https://en.wikipedia.org/wiki/Protease protease] complex. (This structure is similar to yeast [https://www.yeastgenome.org/locus/S000000118 Pim1] )<br />
The six Lon monomers are forming three pairs of legs owned by the N-terminal domain of the protein. This structure is emerging of the protein as a trimer of dimers <ref>Kutejová, Eva. « Mitochondrial Lon protease-unique structure and essential function in mammalian cells ». Integrative Cancer Science and Therapeutics 5, nᵒ 6 (2018). https://doi.org/10.15761/ICST.1000296.<br />
</ref>.<br />
<br><br />
<br><br />
Like many proteins, Lon is a '''flexible''' peptide which has different '''three-dimensional conformations'''. The protein can therefore pass from one conformation to another by hydrolysis of [https://biologydictionary.net/atp/ ATP]<ref>Voos, Wolfgang, et Karen Pollecker. « The Mitochondrial Lon Protease: Novel Functions off the Beaten Track? » Biomolecules 10, nᵒ 2 (7 février 2020). https://doi.org/10.3390/biom10020253.<br />
</ref>.<br />
With these conformational changes, the [https://en.wikipedia.org/wiki/Active_site '''active sites'''] of the Lon protein are protected from the external environment in the oligomeric complex that forms the '''degradation chamber'''.<br />
This form of degradation chamber is also found in bacteria, plants, fungi and metazoan, the similarities with bacteria are most probably due to the [https://en.wikipedia.org/wiki/Symbiogenesis endosymbiotic theory].<br />
<br><br />
<br><br />
This protein has a [https://en.wikipedia.org/wiki/Proteolysis '''proteolytic'''] and [https://en.wikipedia.org/wiki/Chaperone_(protein) '''chaperone''']-like activity, it cannot unfold aggregated proteins, but can participate in the assembling of some complexes). These two enzymatic activities are separated on two polypeptide chains forming a complex or two separate domains on the same polypeptide chain.<br />
<br><br />
The Lon protein has three main distinct domains: the first, the '''N-terminal''' domain, is specialised in '''substrate binding''' and [https://en.wikipedia.org/wiki/Oligomer '''oligomerization''']. The second, called the '''AAA+ domain''' (or A domain) corresponds to the fixation and hydrolysis site of the [https://biologydictionary.net/atp/ATP ATP]. Finally, the third domain located at the '''C-terminal''' is an active serine site leading to '''substrate degradation'''. This is a [https://en.wikipedia.org/wiki/Proteolysis '''proteolytic'''] domain, called domain P <ref>He, Lihong, Dongyang Luo, Fan Yang, Chunhao Li, Xuegong Zhang, Haiteng Deng, et Jing-Ren Zhang. « Multiple domains of bacterial and human Lon proteases define substrate selectivity ». Emerging Microbes & Infections 7 (17 août 2018). https://doi.org/10.1038/s41426-018-0148-4.<br />
</ref>.<br />
<br><br />
Mammalian Lon protein only interacts with '''single-stranded DNA''' (ssDNA) but not dsDNA. There are therefore special sequences for interaction with '''G-rich DNA''' as well as RNA. In addition, the binding of a substrate to the protein stimulates the interaction with the DNA.<br />
[https://en.wikipedia.org/wiki/Mitochondrial_DNA mtDNA] binds to the Lon protein with different affinities depending on the state of the cell and the type of cell meeting the following four parameters <ref>Lu, Bin, Swati Yadav, Parul G. Shah, Tong Liu, Bin Tian, Sebastian Pukszta, Nerissa Villaluna, et al. « Roles for the Human ATP-Dependent Lon Protease in Mitochondrial DNA Maintenance ». Journal of Biological Chemistry 282, nᵒ 24 (15 juin 2007): 17363‑74. https://doi.org/10.1074/jbc.M611540200.<br />
</ref>: <br />
<br><br />
- the single stranding state of mtDNA<br />
<br><br />
- the bioavailability of the mtDNA binding sites<br />
<br><br />
- the affinity of the protein for a given DNA sequence<br />
<br><br />
- the total number of high and low affinity Lon binding sites present</p><br />
<br />
<br />
<br />
<br />
== Structural highlights ==<br />
<br />
From hLon main three domains, the ATPase domain and the C-terminal active site are those which confer to the protein its function.<br />
<br />
<h5>ATP domain</h5><br />
<br />
<p align="justify">The [https://en.wikipedia.org/wiki/ATPase ATPase] domain enables after the '''consumption of an ATP molecule''' to get the required energy for the active site to [https://en.wikipedia.org/wiki/Hydrolysis hydrolyze] protein substrates. It has been demonstrated that the presence of ADP induces a conformational change to obtain an '''asymmetric hexametric ring'''. As a result, the catalytic site reaches its '''open state''' where the protein substrate can bind. ATP most likely replaces ADP from the ATPase domain to cut off the next substrate. In presence of AMP the hexametric ring takes a '''closed conformation''' state suggesting that until either ATP or ADP is present in the environment, hLon has the capacity to perform its catalytic activity<ref>PMID: 27632940</ref>.</p><br />
<br />
<h5>Active site</h5><br />
<br />
<p align="justify">The '''active site''' represent by 2x36 is composed of''' six [https://en.wikipedia.org/wiki/Protomer protomers]''' in the asymmetric unite. One protomer counts nine [https://en.wikipedia.org/wiki/Beta_sheet b-strands] and seven [https://en.wikipedia.org/wiki/Alpha_helix a-helices]. An analysis of the complex’ structure suggested that '''two pair of protomers''' form A:B and C:D dimers and that the '''two''' remaining ones remain '''uncoupled'''. The dimer interface A:B/C:D is mostly linked by one another through '''hydrophilic interactions''', where the a1-helix is packed against the b3-strand and the loop between b7 and b8 makes inter-subunit contacts with b2<ref>PMID: 20222013</ref>.<br />
As all LonA proteins, ''h''Lon catalytic activity relies on a '''Ser-Lys dyad'''. Ser855 on a2 conducts the catalytic cleavage with the assistance of Lys898 on a3 through their [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen-bonding]. The lysine works as a general [https://en.wikipedia.org/wiki/Base_(chemistry) base] along with Thr880 which, in their deprotonated form, abstract the proton from the [https://en.wikipedia.org/wiki/Nucleophile nucleophilic] serine. Those three residues constitute the <scene name='86/868177/Hlonp_catalytic_core/1'>catalytic core</scene>. A characteristic of ''h''LonP is that the [https://en.wikipedia.org/wiki/310_helix 3(10)] helix at the N-terminal end of a2 is able to bring an '''additional residue into the active site''', Asp852. This most likely enables Lys898 [https://en.wikipedia.org/wiki/Acid_dissociation_constant pKa] lowering by creating a [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] environment, and thus, prevents the dyad to cut off protein substrates. This catalytic '''inactive form''' is also supported by the Asp852 and Trp770 residues that contribute to the <scene name='86/868177/Hlonp_closed_catalitic_core/1'>catalytic site obstruction</scene>. Asp852 removal from the active site through conformational changes enables ''h''Lon to reach an open state that can hydrolyze protein substrate through ATP consumption<ref>PMID: 20222013</ref>.</p><br />
<br />
<br />
== Evolutionary conservation ==<br />
<br />
<p align="justify">The Lon proteolytic domain has a highly '''conserved structure'''. Like its orthologues, namely the eubacterium ''[https://fr.wikipedia.org/wiki/Escherichia_coli E. coli]'' ([https://proteopedia.org/wiki/index.php/1rre 1rre]), and the two archaea ''[https://en.wikipedia.org/wiki/Methanocaldococcus_jannaschii M. jannaschii]'' and ''[https://fr.wikipedia.org/wiki/Archaeoglobus_fulgidus A. fulgidus]'', it presents at its C-terminal a '''Ser-Lys dyad''' responsible of the substrate degradation activity. Although ''h''LonP active site resembles mostly to the one of ''Ec''LonP, the b5-sheet is replaced by an '''extension to a2'''. Thus, the N-terminal region of this helix carries the catalytic serine is a [https://en.wikipedia.org/wiki/310_helix 3(10) helix] and not a b-strand. As a consequence, ''h''LonP has the ability to bring the Asp852 into the active site to '''close''' it by forming a hydrogen bond with Lys898, a property already observed in ''Mj''Lon active site. This inactive state likely makes the catalytic serine inaccessible to the substrate and constraints the pKa of the lysine. Other main structural differences are '''loop shifts''' connecting the secondary structure elements b1 and b2, and a1 <ref>PMID: 20222013</ref>.</p><br />
<br />
<br />
== Disease ==<br />
<br />
<p align="justify">Various [https://en.wikipedia.org/wiki/Myopathy myopathy], [https://en.wikipedia.org/wiki/Type_2_diabetes type 2 diabetes], [https://en.wikipedia.org/wiki/Parkinson%27s_disease Parkinson's disease], or [https://en.wikipedia.org/wiki/Alzheimer%27s_disease Alzheimer's disease] are human [https://en.wikipedia.org/wiki/Degenerative_disease degenerative disease] partly due to abnormalities of the mitochondria<ref>Wang, N, S Gottesman, M C Willingham, M M Gottesman, and M R Maurizi. “A Human Mitochondrial ATP-Dependent Protease That Is Highly Homologous to Bacterial Lon Protease.” Proceedings of the National Academy of Sciences 90, no. 23 (December 1, 1993): 11247–51. https://doi.org/10.1073/pnas.90.23.11247.<br />
</ref>. In fact, Lon protease has a role in '''[https://en.wikipedia.org/wiki/Cancer cancer], [https://en.wikipedia.org/wiki/Apoptosis apoptosis] and [https://en.wikipedia.org/wiki/Ageing aging]''' because this protein is an essential part of '''developmental pathways and stress response'''.<br />
<br><br />
<br><br />
[https://en.wikipedia.org/wiki/Mutant Mutant] in Lon decreases the degradation capacity of proteins with abnormal conformations which lead to mitochondrial dysfunction. Mitochondrial dysfunction causes normal cells to become apoptotic, or to aberrant adaptation and selection of hypoxic phenotypes in pathological conditions like cancer<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. <br />
<br><br />
<br><br />
Lon expression is necessary for survival in mammals. Indeed, a [https://en.wikipedia.org/wiki/Zygosity#Homozygous homozygous] [https://en.wikipedia.org/wiki/Deletion_(genetics) deletion] of LONP1 is lethal for early embryonic<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mhttps://proteopedia.org/wiki/skins/common/images/button_extlink.pngitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. Indeed, the [https://rarediseases.info.nih.gov/diseases/1418/codas-syndrome#:~:text=Summary,-Listen&text=Codas%20syndrome%20is%20a%20multiple,Dental%2C%20Auricular%20and%20Skeletal%20anomalies.&text=To%20date%2C%20three%20affected%20children,from%20Brazil)%20have%20been%20reported. CODAS Syndrome] is a rare and multi-system developmental disorder from heterozygous or homozygous mutations in LONP1 where all the affected children were very severely impacted by their disease.<br />
<br><br />
<br><br />
The LONP1 gene is regulated, when the cell undergoes a '''heat shock''', [https://en.wikipedia.org/wiki/Starvation starvation] or oxidative stress the gene is '''up-regulated'''. On the contrary, Lon is '''down-regulated''' with aging, extensive [https://en.wikipedia.org/wiki/Hypoxia hypoxia], and prolonged oxidative stress. So Lon is an important factor in aging and degenerative disease. <br />
<br><br />
A [https://en.wikipedia.org/wiki/Consensus_sequence consensus] binding site of Nuclear Respiratory Factor 2 (NRF-2) is present on the region -623/+1 of the LONP1 promoter which is important for response to [https://en.wikipedia.org/wiki/Reactive_oxygen_species reactive oxygen species] related to oxidative stress. As well as the putative binding site in -2023/-1230 for [https://en.wikipedia.org/wiki/NF-%CE%BABhttps://en.wikipedia.org/wiki/NF-%CE%BAB NF-kB] in LONP1 which consolidate the role of Lon as a stress protein<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Lon Protease Preferentially Degrades Oxidized Mitochondrial Aconitase by an ATP-Stimulated Mechanism.” Nature Cell Biology 4, no. 9 (September 2002): 674–80. https://doi.org/10.1038/ncb836.</ref>. <br />
<br><br />
<br><br />
Research is being done to use Lon as a therapeutic target for the treatment of cancer by developing novel Lon inhibitors.</p><br />
<br />
<br />
</StructureSection><br />
<br />
== References ==<br />
<references/></div>Rose Buhlmannhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1644&diff=3342530Sandbox Reserved 16442021-01-17T19:48:46Z<p>Rose Buhlmann: </p>
<hr />
<div>{{Sandbox_Reserved_ESBS20_}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==2x36 - Structure of the proteolytic domain of the <scene name='86/868177/Structure_hmlon_protease/1'>Human Mitochondrial Lon protease</scene>==<br />
<StructureSection load='2x36' size='340' side='right' caption='Structure of the Human Mitochondrial Lon protease' scene=''><br />
<br />
<br />
== Generalities ==<br />
<br />
<p align="justify">'''2x36''' is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. This domain belongs to the [https://en.wikipedia.org/wiki/Lon_protease_family Lon protease family]. <br />
<br><br />
[https://en.wikipedia.org/wiki/Mitochondrion Mitochondrial] Lon [https://en.wikipedia.org/wiki/Protease protease] is an '''ATP-dependent serine protease''' involved '''in the selective degradation of abnormal proteins'''. [https://en.wikipedia.org/wiki/LONP1 LONP1] situated on chromosome 19 is the nuclear gene encoding mitochondrial Lon protein. The single species of [https://en.wikipedia.org/wiki/Messenger_RNA mRNA] of this protein is found in the mitochondrial matrix. This protein from human tissues has a molecular mass of 100 [https://en.wikipedia.org/wiki/Dalton_(unit) kDA].</p> The proteolytic domain of Lon is the center of the Lon protease activity. <br />
<br><br />
== Function ==<br />
<br />
<p align="justify">The mitochondrial Lon protease is an important regulator of mitochondrial [https://en.wikipedia.org/wiki/Metabolism metabolism] including the maintenance and repair of mitochondrial [https://en.wikipedia.org/wiki/DNA DNA] thanks to its proteolytic domain. This protein is also essential for homeostasis of mitochondria, and by regulating some regulatory proteins which have a short life or damaged proteins. <br />
<br><br />
<br><br />
Lon protease has three main roles<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. <br />
This protein is able to do a '''[https://en.wikipedia.org/wiki/Proteolysis proteolytic] digestion''' of oxidized proteins which allows the renewal of essential mitochondrial enzymes such as [https://en.wikipedia.org/wiki/Aconitase aconitase] or [https://en.wikipedia.org/wiki/TFAM Mitochondrial transcription factor A].<br />
Lon protease is involved in [https://en.wikipedia.org/wiki/Mitochondrial_DNA mtDNA] [https://en.wikipedia.org/wiki/DNA_replication replication] and [https://en.wikipedia.org/w/index.php?title=Mitogenesis&redirect=no mitogenesis] by being a '''mitochondrial [https://en.wikipedia.org/wiki/DNA-binding_protein DNA-bing protein]'''. Human Lon and mtDNA associate at the level of their at least 4 contiguous [https://en.wikipedia.org/wiki/Guanine guanine] sequence and form a [https://en.wikipedia.org/wiki/G-quadruplex G-quadruplex]<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. This G-rich region is the control region for mtDNA replication and transcription<ref>Lu, Bin. “Mitochondrial Lon Protease and Cancer.” Advances in Experimental Medicine and Biology 1038 (2017): 173–82. https://doi.org/10.1007/978-981-10-6674-0_12.</ref>. <br />
<br><br />
Mitochondrial Lon protease interacts with '''[https://en.wikipedia.org/wiki/Chaperone_(protein) protein chaperone]''', notably [https://en.wikipedia.org/wiki/Chaperonin HSP60]-[https://en.wikipedia.org/wiki/Hsp70 Hsp70] complex to protect cell from apoptosis under environmental stress<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>.<br />
<br><br />
The mitochondrial Lon protease is essentially found in the cytoplasmic of mitochondria because [https://en.wikipedia.org/wiki/Amino_acid amino-acid] has a potential mitochondrial targetting presequences<ref>García-Nafría, Javier, Gabriela Ondrovičová, Elena Blagova, Vladimir M Levdikov, Jacob A Bauer, Carolyn K Suzuki, Eva Kutejová, Anthony J Wilkinson, and Keith S Wilson. “Structure of the Catalytic Domain of the Human Mitochondrial Lon Protease: Proposed Relation of Oligomer Formation and Activity.” Protein Science : A Publication of the Protein Society 19, no. 5 (May 2010): 987–99. https://doi.org/10.1002/pro.376.</ref>.<br />
<br><br />
Lon Human protease alternates between cycles of '''being bound to the mitochondrial genome''' and '''being free into the mitochondrial cytoplasm''' thanks to the proteolytic domain where it can degrade abnormal proteins coming from damaged proteins, errors in the synthesis, or [https://en.wikipedia.org/wiki/Protein_folding misfolded] of multimeric proteins. Its inactive conformation prevents uncontrolled proteolysis by the proteolytic domain. <br />
To achieve proteolytic cleavage, the Lon protein has to form a hexamer. <br />
Lon protease has also a role in mtDNA quality control by permits oxidative mitochondrial DNA damage. Sensitivities of H2O2-induced mtDNA damage depend on the proportion of LON<ref>Lu, Bin. “Mitochondrial Lon Protease and Cancer.” Advances in Experimental Medicine and Biology 1038 (2017): 173–82. https://doi.org/10.1007/978-981-10-6674-0_12.</ref>. <br />
Other ATP-dependent proteases are found in eukaryotic cells and organelles like [https://en.wikipedia.org/wiki/Proteasome_endopeptidase_complex 26S protease] which uses [https://en.wikipedia.org/wiki/ATP_hydrolysis ATP hydrolysis] for conjugation or ubiquitin for example.</p><br />
<br><br />
<br />
== General structure ==<br />
<br />
<p align="justify">Lon proteins are grouped into two families, '''LonA''' and '''LonB'''. The human protein LonP1 is part of the LonA proteins <ref>« The N-terminal domain plays a crucial role in the structure of a full-length human mitochondrial Lon protease | Scientific Reports ». Consulté le 13 janvier 2021. https://www.nature.com/articles/srep33631.<br />
</ref>. This protein has three isoforms obtained by [https://en.wikipedia.org/wiki/Alternative_splicing alternative splicing] of the portion of DNA coding for this protein <ref>He, Lihong, Dongyang Luo, Fan Yang, Chunhao Li, Xuegong Zhang, Haiteng Deng, et Jing-Ren Zhang. « Multiple domains of bacterial and human Lon proteases define substrate selectivity ». Emerging Microbes & Infections 7 (17 août 2018). https://doi.org/10.1038/s41426-018-0148-4.<br />
</ref>.<br />
Globally there is a great diversity of Lon proteins, but they are all organized in an oligomeric ring structure, mostly hexameric structure with identical subunits.<br />
Lon proteins are therefore an hexameric chambered [https://en.wikipedia.org/wiki/Protease protease] complex. (This structure is similar to yeast [https://www.yeastgenome.org/locus/S000000118 Pim1] )<br />
The six Lon monomers are forming three pairs of legs owned by the N-terminal domain of the protein. This structure is emerging of the protein as a trimer of dimers <ref>Kutejová, Eva. « Mitochondrial Lon protease-unique structure and essential function in mammalian cells ». Integrative Cancer Science and Therapeutics 5, nᵒ 6 (2018). https://doi.org/10.15761/ICST.1000296.<br />
</ref>.<br />
<br><br />
<br><br />
Like many proteins, Lon is a '''flexible''' peptide which has different '''three-dimensional conformations'''. The protein can therefore pass from one conformation to another by hydrolysis of [https://biologydictionary.net/atp/ ATP]<ref>Voos, Wolfgang, et Karen Pollecker. « The Mitochondrial Lon Protease: Novel Functions off the Beaten Track? » Biomolecules 10, nᵒ 2 (7 février 2020). https://doi.org/10.3390/biom10020253.<br />
</ref>.<br />
With these conformational changes, the [https://en.wikipedia.org/wiki/Active_site '''active sites'''] of the Lon protein are protected from the external environment in the oligomeric complex that forms the '''degradation chamber'''.<br />
This form of degradation chamber is also found in bacteria, plants, fungi and metazoan, the similarities with bacteria are most probably due to the [https://en.wikipedia.org/wiki/Symbiogenesis endosymbiotic theory].<br />
<br><br />
<br><br />
This protein has a [https://en.wikipedia.org/wiki/Proteolysis '''proteolytic'''] and [https://en.wikipedia.org/wiki/Chaperone_(protein) '''chaperone''']-like activity, it cannot unfold aggregated proteins, but can participate in the assembling of some complexes). These two enzymatic activities are separated on two polypeptide chains forming a complex or two separate domains on the same polypeptide chain.<br />
<br><br />
The Lon protein has three main distinct domains: the first, the '''N-terminal''' domain, is specialised in '''substrate binding''' and [https://en.wikipedia.org/wiki/Oligomer '''oligomerization''']. The second, called the '''AAA+ domain''' (or A domain) corresponds to the fixation and hydrolysis site of the [https://biologydictionary.net/atp/ATP ATP]. Finally, the third domain located at the '''C-terminal''' is an active serine site leading to '''substrate degradation'''. This is a [https://en.wikipedia.org/wiki/Proteolysis '''proteolytic'''] domain, called domain P <ref>He, Lihong, Dongyang Luo, Fan Yang, Chunhao Li, Xuegong Zhang, Haiteng Deng, et Jing-Ren Zhang. « Multiple domains of bacterial and human Lon proteases define substrate selectivity ». Emerging Microbes & Infections 7 (17 août 2018). https://doi.org/10.1038/s41426-018-0148-4.<br />
</ref>.<br />
<br><br />
Mammalian Lon protein only interacts with '''single-stranded DNA''' (ssDNA) but not dsDNA. There are therefore special sequences for interaction with '''G-rich DNA''' as well as RNA. In addition, the binding of a substrate to the protein stimulates the interaction with the DNA.<br />
[https://en.wikipedia.org/wiki/Mitochondrial_DNA mtDNA] binds to the Lon protein with different affinities depending on the state of the cell and the type of cell meeting the following four parameters <ref>Lu, Bin, Swati Yadav, Parul G. Shah, Tong Liu, Bin Tian, Sebastian Pukszta, Nerissa Villaluna, et al. « Roles for the Human ATP-Dependent Lon Protease in Mitochondrial DNA Maintenance ». Journal of Biological Chemistry 282, nᵒ 24 (15 juin 2007): 17363‑74. https://doi.org/10.1074/jbc.M611540200.<br />
</ref>: <br />
<br><br />
- the single stranding state of mtDNA<br />
<br><br />
- the bioavailability of the mtDNA binding sites<br />
<br><br />
- the affinity of the protein for a given DNA sequence<br />
<br><br />
- the total number of high and low affinity Lon binding sites present</p><br />
<br />
<br />
<br />
<br />
== Structural highlights ==<br />
<br />
From hLon main three domains, the ATPase domain and the C-terminal active site are those which confer to the protein its function.<br />
<br />
<h5>ATP domain</h5><br />
<br />
<p align="justify">The [https://en.wikipedia.org/wiki/ATPase ATPase] domain enables after the '''consumption of an ATP molecule''' to get the required energy for the active site to [https://en.wikipedia.org/wiki/Hydrolysis hydrolyze] protein substrates. It has been demonstrated that the presence of ADP induces a conformational change to obtain an '''asymmetric hexametric ring'''. As a result, the catalytic site reaches its '''open state''' where the protein substrate can bind. ATP most likely replaces ADP from the ATPase domain to cut off the next substrate. In presence of AMP the hexametric ring takes a '''closed conformation''' state suggesting that until either ATP or ADP is present in the environment, hLon has the capacity to perform its catalytic activity<ref>PMID: 27632940</ref>.</p><br />
<br />
<h5>Active site</h5><br />
<br />
<p align="justify">The '''active site''' represent by 2x36 is composed of''' six [https://en.wikipedia.org/wiki/Protomer protomers]''' in the asymmetric unite. One protomer counts nine [https://en.wikipedia.org/wiki/Beta_sheet b-strands] and seven [https://en.wikipedia.org/wiki/Alpha_helix a-helices]. An analysis of the complex’ structure suggested that '''two pair of protomers''' form A:B and C:D dimers and that the '''two''' remaining ones remain '''uncoupled'''. The dimer interface A:B/C:D is mostly linked by one another through '''hydrophilic interactions''', where the a1-helix is packed against the b3-strand and the loop between b7 and b8 makes inter-subunit contacts with b2<ref>PMID: 20222013</ref>.<br />
As all LonA proteins, ''h''Lon catalytic activity relies on a '''Ser-Lys dyad'''. Ser855 on a2 conducts the catalytic cleavage with the assistance of Lys898 on a3 through their [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen-bonding]. The lysine works as a general [https://en.wikipedia.org/wiki/Base_(chemistry) base] along with Thr880 which, in their deprotonated form, abstract the proton from the [https://en.wikipedia.org/wiki/Nucleophile nucleophilic] serine. Those three residues constitute the <scene name='86/868177/Hlonp_catalytic_core/1'>catalytic core</scene>. A characteristic of ''h''LonP is that the [https://en.wikipedia.org/wiki/310_helix 3(10)] helix at the N-terminal end of a2 is able to bring an '''additional residue into the active site''', Asp852. This most likely enables Lys898 [https://en.wikipedia.org/wiki/Acid_dissociation_constant pKa] lowering by creating a [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] environment, and thus, prevents the dyad to cut off protein substrates. This catalytic '''inactive form''' is also supported by the Asp852 and Trp770 residues that contribute to the catalytic site obstruction. Asp852 removal from the active site through conformational changes enables ''h''Lon to reach an open state that can hydrolyze protein substrate through ATP consumption<ref>PMID: 20222013</ref>.</p><br />
<br />
<br />
== Evolutionary conservation ==<br />
<br />
<p align="justify">The Lon proteolytic domain has a highly '''conserved structure'''. Like its orthologues, namely the eubacterium ''[https://fr.wikipedia.org/wiki/Escherichia_coli E. coli]'' ([https://proteopedia.org/wiki/index.php/1rre 1rre]), and the two archaea ''[https://en.wikipedia.org/wiki/Methanocaldococcus_jannaschii M. jannaschii]'' and ''[https://fr.wikipedia.org/wiki/Archaeoglobus_fulgidus A. fulgidus]'', it presents at its C-terminal a '''Ser-Lys dyad''' responsible of the substrate degradation activity. Although ''h''LonP active site resembles mostly to the one of ''Ec''LonP, the b5-sheet is replaced by an '''extension to a2'''. Thus, the N-terminal region of this helix carries the catalytic serine is a [https://en.wikipedia.org/wiki/310_helix 3(10) helix] and not a b-strand. As a consequence, ''h''LonP has the ability to bring the Asp852 into the active site to '''close''' it by forming a hydrogen bond with Lys898, a property already observed in ''Mj''Lon active site. This inactive state likely makes the catalytic serine inaccessible to the substrate and constraints the pKa of the lysine. Other main structural differences are '''loop shifts''' connecting the secondary structure elements b1 and b2, and a1 <ref>PMID: 20222013</ref>.</p><br />
<br />
<br />
== Disease ==<br />
<br />
<p align="justify">Various [https://en.wikipedia.org/wiki/Myopathy myopathy], [https://en.wikipedia.org/wiki/Type_2_diabetes type 2 diabetes], [https://en.wikipedia.org/wiki/Parkinson%27s_disease Parkinson's disease], or [https://en.wikipedia.org/wiki/Alzheimer%27s_disease Alzheimer's disease] are human [https://en.wikipedia.org/wiki/Degenerative_disease degenerative disease] partly due to abnormalities of the mitochondria<ref>Wang, N, S Gottesman, M C Willingham, M M Gottesman, and M R Maurizi. “A Human Mitochondrial ATP-Dependent Protease That Is Highly Homologous to Bacterial Lon Protease.” Proceedings of the National Academy of Sciences 90, no. 23 (December 1, 1993): 11247–51. https://doi.org/10.1073/pnas.90.23.11247.<br />
</ref>. In fact, Lon protease has a role in '''[https://en.wikipedia.org/wiki/Cancer cancer], [https://en.wikipedia.org/wiki/Apoptosis apoptosis] and [https://en.wikipedia.org/wiki/Ageing aging]''' because this protein is an essential part of '''developmental pathways and stress response'''.<br />
<br><br />
<br><br />
[https://en.wikipedia.org/wiki/Mutant Mutant] in Lon decreases the degradation capacity of proteins with abnormal conformations which lead to mitochondrial dysfunction. Mitochondrial dysfunction causes normal cells to become apoptotic, or to aberrant adaptation and selection of hypoxic phenotypes in pathological conditions like cancer<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. <br />
<br><br />
<br><br />
Lon expression is necessary for survival in mammals. Indeed, a [https://en.wikipedia.org/wiki/Zygosity#Homozygous homozygous] [https://en.wikipedia.org/wiki/Deletion_(genetics) deletion] of LONP1 is lethal for early embryonic<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mhttps://proteopedia.org/wiki/skins/common/images/button_extlink.pngitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. Indeed, the [https://rarediseases.info.nih.gov/diseases/1418/codas-syndrome#:~:text=Summary,-Listen&text=Codas%20syndrome%20is%20a%20multiple,Dental%2C%20Auricular%20and%20Skeletal%20anomalies.&text=To%20date%2C%20three%20affected%20children,from%20Brazil)%20have%20been%20reported. CODAS Syndrome] is a rare and multi-system developmental disorder from heterozygous or homozygous mutations in LONP1 where all the affected children were very severely impacted by their disease.<br />
<br><br />
<br><br />
The LONP1 gene is regulated, when the cell undergoes a '''heat shock''', [https://en.wikipedia.org/wiki/Starvation starvation] or oxidative stress the gene is '''up-regulated'''. On the contrary, Lon is '''down-regulated''' with aging, extensive [https://en.wikipedia.org/wiki/Hypoxia hypoxia], and prolonged oxidative stress. So Lon is an important factor in aging and degenerative disease. <br />
<br><br />
A [https://en.wikipedia.org/wiki/Consensus_sequence consensus] binding site of Nuclear Respiratory Factor 2 (NRF-2) is present on the region -623/+1 of the LONP1 promoter which is important for response to [https://en.wikipedia.org/wiki/Reactive_oxygen_species reactive oxygen species] related to oxidative stress. As well as the putative binding site in -2023/-1230 for [https://en.wikipedia.org/wiki/NF-%CE%BABhttps://en.wikipedia.org/wiki/NF-%CE%BAB NF-kB] in LONP1 which consolidate the role of Lon as a stress protein<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Lon Protease Preferentially Degrades Oxidized Mitochondrial Aconitase by an ATP-Stimulated Mechanism.” Nature Cell Biology 4, no. 9 (September 2002): 674–80. https://doi.org/10.1038/ncb836.</ref>. <br />
<br><br />
<br><br />
Research is being done to use Lon as a therapeutic target for the treatment of cancer by developing novel Lon inhibitors.</p><br />
<br />
<br />
</StructureSection><br />
<br />
== References ==<br />
<references/></div>Rose Buhlmannhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1644&diff=3342529Sandbox Reserved 16442021-01-17T18:55:03Z<p>Rose Buhlmann: </p>
<hr />
<div>{{Sandbox_Reserved_ESBS20_}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==2x36 - Structure of the proteolytic domain of the <scene name='86/868177/Structure_hmlon_protease/1'>Human Mitochondrial Lon protease</scene>==<br />
<StructureSection load='2x36' size='340' side='right' caption='Structure of the Human Mitochondrial Lon protease' scene=''><br />
<br />
<br />
== Generalities ==<br />
<br />
<p align="justify">'''2x36''' is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. This domain belongs to the [https://en.wikipedia.org/wiki/Lon_protease_family Lon protease family]. <br />
<br><br />
[https://en.wikipedia.org/wiki/Mitochondrion Mitochondrial] Lon [https://en.wikipedia.org/wiki/Protease protease] is an '''ATP-dependent serine protease''' involved '''in the selective degradation of abnormal proteins'''. [https://en.wikipedia.org/wiki/LONP1 LONP1] situated on chromosome 19 is the nuclear gene encoding mitochondrial Lon protein. The single species of [https://en.wikipedia.org/wiki/Messenger_RNA mRNA] of this protein is found in the mitochondrial matrix. This protein from human tissues has a molecular mass of 100 [https://en.wikipedia.org/wiki/Dalton_(unit) kDA].</p> The proteolytic domain of Lon is the center of the Lon protease activity. <br />
<br><br />
== Function ==<br />
<br />
<p align="justify">The mitochondrial Lon protease is an important regulator of mitochondrial [https://en.wikipedia.org/wiki/Metabolism metabolism] including the maintenance and repair of mitochondrial [https://en.wikipedia.org/wiki/DNA DNA] thanks to its proteolytic domain. This protein is also essential for homeostasis of mitochondria, and by regulating some regulatory proteins which have a short life or damaged proteins. <br />
<br><br />
<br><br />
Lon protease has three main roles<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. <br />
This protein is able to do a '''[https://en.wikipedia.org/wiki/Proteolysis proteolytic] digestion''' of oxidized proteins which allows the renewal of essential mitochondrial enzymes such as [https://en.wikipedia.org/wiki/Aconitase aconitase] or [https://en.wikipedia.org/wiki/TFAM Mitochondrial transcription factor A].<br />
Lon protease is involved in [https://en.wikipedia.org/wiki/Mitochondrial_DNA mtDNA] [https://en.wikipedia.org/wiki/DNA_replication replication] and [https://en.wikipedia.org/w/index.php?title=Mitogenesis&redirect=no mitogenesis] by being a '''mitochondrial [https://en.wikipedia.org/wiki/DNA-binding_protein DNA-bing protein]'''. Human Lon and mtDNA associate at the level of their at least 4 contiguous [https://en.wikipedia.org/wiki/Guanine guanine] sequence and form a [https://en.wikipedia.org/wiki/G-quadruplex G-quadruplex]<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. This G-rich region is the control region for mtDNA replication and transcription<ref>Lu, Bin. “Mitochondrial Lon Protease and Cancer.” Advances in Experimental Medicine and Biology 1038 (2017): 173–82. https://doi.org/10.1007/978-981-10-6674-0_12.</ref>. <br />
<br><br />
Mitochondrial Lon protease interacts with '''[https://en.wikipedia.org/wiki/Chaperone_(protein) protein chaperone]''', notably [https://en.wikipedia.org/wiki/Chaperonin HSP60]-[https://en.wikipedia.org/wiki/Hsp70 Hsp70] complex to protect cell from apoptosis under environmental stress<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>.<br />
<br><br />
The mitochondrial Lon protease is essentially found in the cytoplasmic of mitochondria because [https://en.wikipedia.org/wiki/Amino_acid amino-acid] has a potential mitochondrial targetting presequences<ref>García-Nafría, Javier, Gabriela Ondrovičová, Elena Blagova, Vladimir M Levdikov, Jacob A Bauer, Carolyn K Suzuki, Eva Kutejová, Anthony J Wilkinson, and Keith S Wilson. “Structure of the Catalytic Domain of the Human Mitochondrial Lon Protease: Proposed Relation of Oligomer Formation and Activity.” Protein Science : A Publication of the Protein Society 19, no. 5 (May 2010): 987–99. https://doi.org/10.1002/pro.376.</ref>.<br />
<br><br />
Lon Human protease alternates between cycles of '''being bound to the mitochondrial genome''' and '''being free into the mitochondrial cytoplasm''' thanks to the proteolytic domain where it can degrade abnormal proteins coming from damaged proteins, errors in the synthesis, or [https://en.wikipedia.org/wiki/Protein_folding misfolded] of multimeric proteins. Its inactive conformation prevents uncontrolled proteolysis by the proteolytic domain. <br />
To achieve proteolytic cleavage, the Lon protein has to form a hexamer. <br />
Lon protease has also a role in mtDNA quality control by permits oxidative mitochondrial DNA damage. Sensitivities of H2O2-induced mtDNA damage depend on the proportion of LON<ref>Lu, Bin. “Mitochondrial Lon Protease and Cancer.” Advances in Experimental Medicine and Biology 1038 (2017): 173–82. https://doi.org/10.1007/978-981-10-6674-0_12.</ref>. <br />
Other ATP-dependent proteases are found in eukaryotic cells and organelles like [https://en.wikipedia.org/wiki/Proteasome_endopeptidase_complex 26S protease] which uses [https://en.wikipedia.org/wiki/ATP_hydrolysis ATP hydrolysis] for conjugation or ubiquitin for example.</p><br />
<br><br />
<br />
== General structure ==<br />
<br />
<p align="justify">Lon proteins are grouped into two families, '''LonA''' and '''LonB'''. The human protein LonP1 is part of the LonA proteins <ref>« The N-terminal domain plays a crucial role in the structure of a full-length human mitochondrial Lon protease | Scientific Reports ». Consulté le 13 janvier 2021. https://www.nature.com/articles/srep33631.<br />
</ref>. This protein has three isoforms obtained by [https://en.wikipedia.org/wiki/Alternative_splicing alternative splicing] of the portion of DNA coding for this protein <ref>He, Lihong, Dongyang Luo, Fan Yang, Chunhao Li, Xuegong Zhang, Haiteng Deng, et Jing-Ren Zhang. « Multiple domains of bacterial and human Lon proteases define substrate selectivity ». Emerging Microbes & Infections 7 (17 août 2018). https://doi.org/10.1038/s41426-018-0148-4.<br />
</ref>.<br />
Globally there is a great diversity of Lon proteins, but they are all organized in an oligomeric ring structure, mostly hexameric structure with identical subunits.<br />
Lon proteins are therefore an hexameric chambered [https://en.wikipedia.org/wiki/Protease protease] complex. (This structure is similar to yeast [https://www.yeastgenome.org/locus/S000000118 Pim1] )<br />
The six Lon monomers are forming three pairs of legs owned by the N-terminal domain of the protein. This structure is emerging of the protein as a trimer of dimers <ref>Kutejová, Eva. « Mitochondrial Lon protease-unique structure and essential function in mammalian cells ». Integrative Cancer Science and Therapeutics 5, nᵒ 6 (2018). https://doi.org/10.15761/ICST.1000296.<br />
</ref>.<br />
<br><br />
<br><br />
Like many proteins, Lon is a '''flexible''' peptide which has different '''three-dimensional conformations'''. The protein can therefore pass from one conformation to another by hydrolysis of [https://biologydictionary.net/atp/ ATP]<ref>Voos, Wolfgang, et Karen Pollecker. « The Mitochondrial Lon Protease: Novel Functions off the Beaten Track? » Biomolecules 10, nᵒ 2 (7 février 2020). https://doi.org/10.3390/biom10020253.<br />
</ref>.<br />
With these conformational changes, the [https://en.wikipedia.org/wiki/Active_site '''active sites'''] of the Lon protein are protected from the external environment in the oligomeric complex that forms the '''degradation chamber'''.<br />
This form of degradation chamber is also found in bacteria, plants, fungi and metazoan, the similarities with bacteria are most probably due to the [https://en.wikipedia.org/wiki/Symbiogenesis endosymbiotic theory].<br />
<br><br />
<br><br />
This protein has a [https://en.wikipedia.org/wiki/Proteolysis '''proteolytic'''] and [https://en.wikipedia.org/wiki/Chaperone_(protein) '''chaperone''']-like activity, it cannot unfold aggregated proteins, but can participate in the assembling of some complexes). These two enzymatic activities are separated on two polypeptide chains forming a complex or two separate domains on the same polypeptide chain.<br />
<br><br />
The Lon protein has three main distinct domains: the first, the '''N-terminal''' domain, is specialised in '''substrate binding''' and [https://en.wikipedia.org/wiki/Oligomer '''oligomerization''']. The second, called the '''AAA+ domain''' (or A domain) corresponds to the fixation and hydrolysis site of the [https://biologydictionary.net/atp/ATP ATP]. Finally, the third domain located at the '''C-terminal''' is an active serine site leading to '''substrate degradation'''. This is a [https://en.wikipedia.org/wiki/Proteolysis '''proteolytic'''] domain, called domain P <ref>He, Lihong, Dongyang Luo, Fan Yang, Chunhao Li, Xuegong Zhang, Haiteng Deng, et Jing-Ren Zhang. « Multiple domains of bacterial and human Lon proteases define substrate selectivity ». Emerging Microbes & Infections 7 (17 août 2018). https://doi.org/10.1038/s41426-018-0148-4.<br />
</ref>.<br />
<br><br />
Mammalian Lon protein only interacts with '''single-stranded DNA''' (ssDNA) but not dsDNA. There are therefore special sequences for interaction with '''G-rich DNA''' as well as RNA. In addition, the binding of a substrate to the protein stimulates the interaction with the DNA.<br />
[https://en.wikipedia.org/wiki/Mitochondrial_DNA mtDNA] binds to the Lon protein with different affinities depending on the state of the cell and the type of cell meeting the following four parameters <ref>Lu, Bin, Swati Yadav, Parul G. Shah, Tong Liu, Bin Tian, Sebastian Pukszta, Nerissa Villaluna, et al. « Roles for the Human ATP-Dependent Lon Protease in Mitochondrial DNA Maintenance ». Journal of Biological Chemistry 282, nᵒ 24 (15 juin 2007): 17363‑74. https://doi.org/10.1074/jbc.M611540200.<br />
</ref>: <br />
<br><br />
- the single stranding state of mtDNA<br />
<br><br />
- the bioavailability of the mtDNA binding sites<br />
<br><br />
- the affinity of the protein for a given DNA sequence<br />
<br><br />
- the total number of high and low affinity Lon binding sites present</p><br />
<br />
<br />
<br />
<br />
== Structural highlights ==<br />
<br />
From hLon main three domains, the ATPase domain and the C-terminal active site are those which confer to the protein its function.<br />
<br />
<h5>ATP domain</h5><br />
<br />
<p align="justify">The [https://en.wikipedia.org/wiki/ATPase ATPase] domain enables after the '''consumption of an ATP molecule''' to get the required energy for the active site to [https://en.wikipedia.org/wiki/Hydrolysis hydrolyze] protein substrates. It has been demonstrated that the presence of ADP induces a conformational change to obtain an '''asymmetric hexametric ring'''. As a result, the catalytic site reaches its '''open state''' where the protein substrate can bind. ATP most likely replaces ADP from the ATPase domain to cut off the next substrate. In presence of AMP the hexametric ring takes a '''closed conformation''' state suggesting that until either ATP or ADP is present in the environment, hLon has the capacity to perform its catalytic activity<ref>PMID: 27632940</ref>.</p><br />
<br />
<h5>Active site</h5><br />
<br />
<p align="justify">The '''active site''' represent by 2x36 is composed of''' six [https://en.wikipedia.org/wiki/Protomer protomers]''' in the asymmetric unite. One protomer counts nine [https://en.wikipedia.org/wiki/Beta_sheet b-strands] and seven [https://en.wikipedia.org/wiki/Alpha_helix a-helices]. An analysis of the complex’ structure suggested that '''two pair of protomers''' form A:B and C:D dimers and that the '''two''' remaining ones remain '''uncoupled'''. The dimer interface A:B/C:D is mostly linked by one another through '''hydrophilic interactions''', where the a1-helix is packed against the b3-strand and the loop between b7 and b8 makes inter-subunit contacts with b2<ref>PMID: 20222013</ref>.<br />
As all LonA proteins, ''h''Lon catalytic activity relies on a '''Ser-Lys dyad'''. Ser855 on a2 conducts the catalytic cleavage with the assistance of Lys898 on a3 through their [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen-bonding]. The lysine works as a general [https://en.wikipedia.org/wiki/Base_(chemistry) base] along with Thr880 which, in their deprotonated form, abstract the proton from the [https://en.wikipedia.org/wiki/Nucleophile nucleophilic] serine. Those three residues constitute the catalytic core. A characteristic of ''h''LonP is that the [https://en.wikipedia.org/wiki/310_helix 3(10)] helix at the N-terminal end of a2 is able to bring an '''additional residue into the active site''', Asp852. This most likely enables Lys898 [https://en.wikipedia.org/wiki/Acid_dissociation_constant pKa] lowering by creating a [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] environment, and thus, prevents the dyad to cut off protein substrates. This catalytic '''inactive form''' is also supported by the Asp852 and Trp770 residues that contribute to the catalytic site obstruction. Asp852 removal from the active site through conformational changes enables ''h''Lon to reach an open state that can hydrolyze protein substrate through ATP consumption<ref>PMID: 20222013</ref>.</p><br />
<br />
<br />
== Evolutionary conservation ==<br />
<br />
<p align="justify">The Lon proteolytic domain has a highly '''conserved structure'''. Like its orthologues, namely the eubacterium ''[https://fr.wikipedia.org/wiki/Escherichia_coli E. coli]'' ([https://proteopedia.org/wiki/index.php/1rre 1rre]), and the two archaea ''[https://en.wikipedia.org/wiki/Methanocaldococcus_jannaschii M. jannaschii]'' and ''[https://fr.wikipedia.org/wiki/Archaeoglobus_fulgidus A. fulgidus]'', it presents at its C-terminal a '''Ser-Lys dyad''' responsible of the substrate degradation activity. Although ''h''LonP active site resembles mostly to the one of ''Ec''LonP, the b5-sheet is replaced by an '''extension to a2'''. Thus, the N-terminal region of this helix carries the catalytic serine is a [https://en.wikipedia.org/wiki/310_helix 3(10) helix] and not a b-strand. As a consequence, ''h''LonP has the ability to bring the Asp852 into the active site to '''close''' it by forming a hydrogen bond with Lys898, a property already observed in ''Mj''Lon active site. This inactive state likely makes the catalytic serine inaccessible to the substrate and constraints the pKa of the lysine. Other main structural differences are '''loop shifts''' connecting the secondary structure elements b1 and b2, and a1 <ref>PMID: 20222013</ref>.</p><br />
<br />
<br />
== Disease ==<br />
<br />
<p align="justify">Various [https://en.wikipedia.org/wiki/Myopathy myopathy], [https://en.wikipedia.org/wiki/Type_2_diabetes type 2 diabetes], [https://en.wikipedia.org/wiki/Parkinson%27s_disease Parkinson's disease], or [https://en.wikipedia.org/wiki/Alzheimer%27s_disease Alzheimer's disease] are human [https://en.wikipedia.org/wiki/Degenerative_disease degenerative disease] partly due to abnormalities of the mitochondria<ref>Wang, N, S Gottesman, M C Willingham, M M Gottesman, and M R Maurizi. “A Human Mitochondrial ATP-Dependent Protease That Is Highly Homologous to Bacterial Lon Protease.” Proceedings of the National Academy of Sciences 90, no. 23 (December 1, 1993): 11247–51. https://doi.org/10.1073/pnas.90.23.11247.<br />
</ref>. In fact, Lon protease has a role in '''[https://en.wikipedia.org/wiki/Cancer cancer], [https://en.wikipedia.org/wiki/Apoptosis apoptosis] and [https://en.wikipedia.org/wiki/Ageing aging]''' because this protein is an essential part of '''developmental pathways and stress response'''.<br />
<br><br />
<br><br />
[https://en.wikipedia.org/wiki/Mutant Mutant] in Lon decreases the degradation capacity of proteins with abnormal conformations which lead to mitochondrial dysfunction. Mitochondrial dysfunction causes normal cells to become apoptotic, or to aberrant adaptation and selection of hypoxic phenotypes in pathological conditions like cancer<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. <br />
<br><br />
<br><br />
Lon expression is necessary for survival in mammals. Indeed, a [https://en.wikipedia.org/wiki/Zygosity#Homozygous homozygous] [https://en.wikipedia.org/wiki/Deletion_(genetics) deletion] of LONP1 is lethal for early embryonic<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mhttps://proteopedia.org/wiki/skins/common/images/button_extlink.pngitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. Indeed, the [https://rarediseases.info.nih.gov/diseases/1418/codas-syndrome#:~:text=Summary,-Listen&text=Codas%20syndrome%20is%20a%20multiple,Dental%2C%20Auricular%20and%20Skeletal%20anomalies.&text=To%20date%2C%20three%20affected%20children,from%20Brazil)%20have%20been%20reported. CODAS Syndrome] is a rare and multi-system developmental disorder from heterozygous or homozygous mutations in LONP1 where all the affected children were very severely impacted by their disease.<br />
<br><br />
<br><br />
The LONP1 gene is regulated, when the cell undergoes a '''heat shock''', [https://en.wikipedia.org/wiki/Starvation starvation] or oxidative stress the gene is '''up-regulated'''. On the contrary, Lon is '''down-regulated''' with aging, extensive [https://en.wikipedia.org/wiki/Hypoxia hypoxia], and prolonged oxidative stress. So Lon is an important factor in aging and degenerative disease. <br />
<br><br />
A [https://en.wikipedia.org/wiki/Consensus_sequence consensus] binding site of Nuclear Respiratory Factor 2 (NRF-2) is present on the region -623/+1 of the LONP1 promoter which is important for response to [https://en.wikipedia.org/wiki/Reactive_oxygen_species reactive oxygen species] related to oxidative stress. As well as the putative binding site in -2023/-1230 for [https://en.wikipedia.org/wiki/NF-%CE%BABhttps://en.wikipedia.org/wiki/NF-%CE%BAB NF-kB] in LONP1 which consolidate the role of Lon as a stress protein<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Lon Protease Preferentially Degrades Oxidized Mitochondrial Aconitase by an ATP-Stimulated Mechanism.” Nature Cell Biology 4, no. 9 (September 2002): 674–80. https://doi.org/10.1038/ncb836.</ref>. <br />
<br><br />
<br><br />
Research is being done to use Lon as a therapeutic target for the treatment of cancer by developing novel Lon inhibitors.</p><br />
<br />
<br />
</StructureSection><br />
<br />
== References ==<br />
<references/></div>Rose Buhlmannhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1644&diff=3342286Sandbox Reserved 16442021-01-14T18:37:25Z<p>Rose Buhlmann: </p>
<hr />
<div>{{Sandbox_Reserved_ESBS20_}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==2x36 - Structure of the proteolytic domain of the <scene name='86/868177/Structure_hmlon_protease/1'>Human Mitochondrial Lon protease</scene>==<br />
<StructureSection load='2x36' size='340' side='right' caption='Structure of the Human Mitochondrial Lon protease' scene=''><br />
<br />
<p align="justify">'''2x36''' is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. This domain belongs to the [https://en.wikipedia.org/wiki/Lon_protease_family Lon protease family]. <br />
<br><br />
[https://en.wikipedia.org/wiki/Mitochondrion Mitochondrial] Lon [https://en.wikipedia.org/wiki/Protease protease] is an '''ATP-dependent serine protease''' involved '''in the selective degradation of abnormal proteins'''. [https://en.wikipedia.org/wiki/LONP1 LONP1] situated on chromosome 19 is the nuclear gene encoding mitochondrial Lon protein. The single species of [https://en.wikipedia.org/wiki/Messenger_RNA mRNA] of this protein is found in the mitochondrial matrix. This protein from human tissues has a molecular mass of 100 [https://en.wikipedia.org/wiki/Dalton_(unit) kDA].</p><br />
<br><br />
== Function ==<br />
<br />
<p align="justify">The mitochondrial Lon protease is an important regulator of mitochondrial [https://en.wikipedia.org/wiki/Metabolism metabolism] including the maintenance and repair of mitochondrial [https://en.wikipedia.org/wiki/DNA DNA]. This protein is also essential for homeostasis of mitochondria, and by regulating some regulatory proteins which have a short life or damaged proteins. <br />
<br><br />
<br><br />
Lon protease has three main roles<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. <br />
This protein is able to do a '''[https://en.wikipedia.org/wiki/Proteolysis proteolytic] digestion''' of oxidized proteins which allows the renewal of essential mitochondrial enzymes such as [https://en.wikipedia.org/wiki/Aconitase aconitase] or [https://en.wikipedia.org/wiki/TFAM Mitochondrial transcription factor A].<br />
Lon protease is involved in [https://en.wikipedia.org/wiki/Mitochondrial_DNA mtDNA] [https://en.wikipedia.org/wiki/DNA_replication replication] and [https://en.wikipedia.org/w/index.php?title=Mitogenesis&redirect=no mitogenesis] by being a '''mitochondrial [https://en.wikipedia.org/wiki/DNA-binding_protein DNA-bing protein]'''. Human Lon and mtDNA associate at the level of their at least 4 contiguous [https://en.wikipedia.org/wiki/Guanine guanine] sequence and form a [https://en.wikipedia.org/wiki/G-quadruplex G-quadruplex]<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. This G-rich region is the control region for mtDNA replication and transcription<ref>Lu, Bin. “Mitochondrial Lon Protease and Cancer.” Advances in Experimental Medicine and Biology 1038 (2017): 173–82. https://doi.org/10.1007/978-981-10-6674-0_12.</ref>. <br />
<br><br />
Mitochondrial Lon protease interacts with '''[https://en.wikipedia.org/wiki/Chaperone_(protein) protein chaperone]''', notably [https://en.wikipedia.org/wiki/Chaperonin HSP60]-[https://en.wikipedia.org/wiki/Hsp70 Hsp70] complex to protect cell from apoptosis under environmental stress<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>.<br />
<br><br />
The mitochondrial Lon protease is essentially found in the cytoplasmic of mitochondria because [https://en.wikipedia.org/wiki/Amino_acid amino-acid] has a potential mitochondrial targetting presequences<ref>García-Nafría, Javier, Gabriela Ondrovičová, Elena Blagova, Vladimir M Levdikov, Jacob A Bauer, Carolyn K Suzuki, Eva Kutejová, Anthony J Wilkinson, and Keith S Wilson. “Structure of the Catalytic Domain of the Human Mitochondrial Lon Protease: Proposed Relation of Oligomer Formation and Activity.” Protein Science : A Publication of the Protein Society 19, no. 5 (May 2010): 987–99. https://doi.org/10.1002/pro.376.</ref>.<br />
<br><br />
Lon Human protease alternates between cycles of '''being bound to the mitochondrial genome''' and '''being free into the mitochondrial cytoplasm''' where it can degrade abnormal proteins coming from damaged proteins, errors in the synthesis, or [https://en.wikipedia.org/wiki/Protein_folding misfolded] of multimeric proteins. Its inactive conformation prevents uncontrolled proteolysis. <br />
To achieve proteolytic cleavage, the Lon protein has to form a hexamer. <br />
Lon protease has also a role in mtDNA quality control by permits oxidative mitochondrial DNA damage. Sensitivities of H2O2-induced mtDNA damage depend on the proportion of LON<ref>Lu, Bin. “Mitochondrial Lon Protease and Cancer.” Advances in Experimental Medicine and Biology 1038 (2017): 173–82. https://doi.org/10.1007/978-981-10-6674-0_12.</ref>. <br />
Other ATP-dependent proteases are found in eukaryotic cells and organelles like [https://en.wikipedia.org/wiki/Proteasome_endopeptidase_complex 26S protease] which uses [https://en.wikipedia.org/wiki/ATP_hydrolysis ATP hydrolysis] for conjugation or ubiquitin for example.</p><br />
<br><br />
<br />
== General structure ==<br />
<br />
<p align="justify">Lon proteins are grouped into two families, '''LonA''' and '''LonB'''. The human protein LonP1 is part of the LonA proteins <ref>« The N-terminal domain plays a crucial role in the structure of a full-length human mitochondrial Lon protease | Scientific Reports ». Consulté le 13 janvier 2021. https://www.nature.com/articles/srep33631.<br />
</ref>. This protein has three isoforms obtained by [https://en.wikipedia.org/wiki/Alternative_splicing alternative splicing] of the portion of DNA coding for this protein <ref>He, Lihong, Dongyang Luo, Fan Yang, Chunhao Li, Xuegong Zhang, Haiteng Deng, et Jing-Ren Zhang. « Multiple domains of bacterial and human Lon proteases define substrate selectivity ». Emerging Microbes & Infections 7 (17 août 2018). https://doi.org/10.1038/s41426-018-0148-4.<br />
</ref>.<br />
Globally there is a great diversity of Lon proteins, but they are all organised in an oligomeric ring structure, mostly hexameric structure with identical subunits.<br />
Lon proteins are therefore an hexameric chambered [https://en.wikipedia.org/wiki/Protease protease] complex. (This structure is similar with yeast [https://www.yeastgenome.org/locus/S000000118 Pim1] )<br />
The six Lon monomers are forming three pairs of legs owned by the N-terminal domain of the protein. This structure is emerging of the protein as a trimer of dimers <ref>Kutejová, Eva. « Mitochondrial Lon protease-unique structure and essential function in mammalian cells ». Integrative Cancer Science and Therapeutics 5, nᵒ 6 (2018). https://doi.org/10.15761/ICST.1000296.<br />
</ref>.<br />
<br><br />
Like many proteins, Lon is a '''flexible''' peptide which has different '''three-dimensional conformations'''. The protein can therefore pass from one conformation to another by hydrolysis of [https://biologydictionary.net/atp/ ATP]<ref>Voos, Wolfgang, et Karen Pollecker. « The Mitochondrial Lon Protease: Novel Functions off the Beaten Track? » Biomolecules 10, nᵒ 2 (7 février 2020). https://doi.org/10.3390/biom10020253.<br />
</ref>.<br />
With these conformational changes, the [https://en.wikipedia.org/wiki/Active_site '''active sites'''] of the Lon protein are protected from the external environment in the oligomeric complex that forms the '''degradation chamber'''.<br />
This form of degradation chamber is also found in bacteria, plants, fungi and metazoan, the similarities with bacteria are most probably due to the [https://en.wikipedia.org/wiki/Symbiogenesis endosymbiotic theory].<br />
<br><br />
<br><br />
This protein has a [https://en.wikipedia.org/wiki/Proteolysis '''proteolytic'''] and [https://en.wikipedia.org/wiki/Chaperone_(protein) '''chaperone''']-like activity, it cannot unfold aggregated proteins, but can participate in the assembling of some complexes). These two enzymatic activities are separated on two polypeptide chains forming a complex or two separate domains on the same polypeptide chain.<br />
<br><br />
The Lon protein has three main distinct domains: the first, the '''N-terminal''' domain, is specialised in '''substrate binding''' and [https://en.wikipedia.org/wiki/Oligomer '''oligomerization''']. The second, called the '''AAA+ domain''' (or A domain) corresponds to the fixation and hydrolysis site of the [https://biologydictionary.net/atp/ATP ATP]. Finally, the third domain located at the '''C-terminal''' is an active serine site leading to '''substrate degradation'''. This is a [https://en.wikipedia.org/wiki/Proteolysis '''proteolytic'''] domain, called domain P <ref>He, Lihong, Dongyang Luo, Fan Yang, Chunhao Li, Xuegong Zhang, Haiteng Deng, et Jing-Ren Zhang. « Multiple domains of bacterial and human Lon proteases define substrate selectivity ». Emerging Microbes & Infections 7 (17 août 2018). https://doi.org/10.1038/s41426-018-0148-4.<br />
</ref>.<br />
<br><br />
Mammalian Lon protein only interacts with '''single-stranded DNA''' (ssDNA) but not dsDNA. There are therefore special sequences for interaction with '''G-rich DNA''' as well as RNA. In addition, the binding of a substrate to the protein stimulates the interaction with the DNA.<br />
[https://en.wikipedia.org/wiki/Mitochondrial_DNA mtDNA] binds to the Lon protein with different affinities depending on the state of the cell and the type of cell meeting the following four parameters <ref>Lu, Bin, Swati Yadav, Parul G. Shah, Tong Liu, Bin Tian, Sebastian Pukszta, Nerissa Villaluna, et al. « Roles for the Human ATP-Dependent Lon Protease in Mitochondrial DNA Maintenance ». Journal of Biological Chemistry 282, nᵒ 24 (15 juin 2007): 17363‑74. https://doi.org/10.1074/jbc.M611540200.<br />
</ref>: <br />
<br><br />
- the single stranding state of mtDNA<br />
<br><br />
- the bioavailability of the mtDNA binding sites<br />
<br><br />
- the affinity of the protein for a given DNA sequence<br />
<br><br />
- the total number of high and low affinity Lon binding sites present</p><br />
<br />
<br />
<br />
<br />
== Structural highlights ==<br />
<br />
From hLon main three domains, the ATPase domain and the C-terminal active site are those which confer to the protein its function.<br />
<br />
The [https://en.wikipedia.org/wiki/ATPase ATPase] domain enables after the '''consumption of an ATP molecule''' to get the required energy for the active site to [https://en.wikipedia.org/wiki/Hydrolysis hydrolyze] protein substrates. It has been demonstrated that the presence of ADP induces a conformational change to obtain an '''asymmetric hexametric ring'''. As a result, the catalytic site reaches its '''open state''' where the protein substrate can bind. ATP most likely replaces ADP from the ATPase domain to cut off the next substrate. In presence of AMP the hexametric ring takes a '''closed conformation''' state suggesting that until either ATP or ADP is present in the environment, hLon has the capacity to perform its catalytic activity<ref>PMID: 27632940</ref>. <br />
<br />
The active site is composed of six [https://en.wikipedia.org/wiki/Protomer protomers] in the asymmetric unite. One protomer counts nine [https://en.wikipedia.org/wiki/Beta_sheet b-strands] and seven [https://en.wikipedia.org/wiki/Alpha_helix a-helices]. An analysis of the complex’ structure suggested that '''two pair of protomers''' form A:B and C:D dimers and that the '''two''' remaining ones remain '''uncoupled'''. The dimer interface A:B/C:D is mostly linked by one another through hydrophilic interactions, where the a1-helix is packed against the b3-strand and the loop between b7 and b8 makes inter-subunit contacts with b2<ref>PMID: 20222013</ref>.<br />
As all LonA proteins, ''h''Lon catalytic activity relies on a '''Ser-Lys dyad'''. Ser855 on a2 conducts the catalytic cleavage with the assistance of Lys898 on a3 through their [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen-bonding]. The lysine works as a general [https://en.wikipedia.org/wiki/Base_(chemistry) base] which, in its deprotonated form, abstracts the proton from the [https://en.wikipedia.org/wiki/Nucleophile nucleophilic] serine. A characteristic of ''h''LonP is that the [https://en.wikipedia.org/wiki/310_helix 3(10)] helix at the N-terminal end of a2 is able to bring an '''additional residue into the active site''', Asp852. This most likely enables Lys898 [https://en.wikipedia.org/wiki/Acid_dissociation_constant pKa] lowering by creating a [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] environment, and thus, prevents the dyad to cut off protein substrates. This catalytic '''inactive form''' is also supported by the Asp852 and Trp770 residues that contribute to the catalytic site obstruction. Asp852 removal from the active site through conformational changes enables ''h''Lon to reach an open state that can hydrolyze protein substrate through ATP consumption<ref>PMID: 20222013</ref>.<br />
<br />
<br />
== Evolutionary conservation ==<br />
<br />
The Lon proteolytic domain has a highly '''conserved structure'''. Like its orthologues, namely the eubacterium ''[https://fr.wikipedia.org/wiki/Escherichia_coli E. coli]'' ([https://proteopedia.org/wiki/index.php/1rre 1rre]), and the two archaea ''[https://en.wikipedia.org/wiki/Methanocaldococcus_jannaschii M. jannaschii]'' and ''[https://fr.wikipedia.org/wiki/Archaeoglobus_fulgidus A. fulgidus]'', it presents at its C-terminal a '''Ser-Lys dyad''' responsible of the substrate degradation activity. Although ''h''LonP active site resembles mostly to the one of ''Ec''LonP, the b5-sheet is replaced by an '''extension to a2'''. Thus, the N-terminal region of this helix carries the catalytic serine is a [https://en.wikipedia.org/wiki/310_helix 3(10) helix] and not a b-strand. As a consequence, ''h''LonP has the ability to bring the Asp852 into the active site to '''close''' it by forming a hydrogen bond with Lys898, a property already observed in ''Mj''Lon active site. This inactive state likely makes the catalytic serine inaccessible to the substrate and constraints the pKa of the lysine. Other main structural differences are '''loop shifts''' connecting the secondary structure elements b1 and b2, and a1 <ref>PMID: 20222013</ref>.<br />
<br />
<br />
== Disease ==<br />
<br />
<p align="justify">Various [https://en.wikipedia.org/wiki/Myopathy myopathy], [https://en.wikipedia.org/wiki/Type_2_diabetes type 2 diabetes], [https://en.wikipedia.org/wiki/Parkinson%27s_disease Parkinson's disease], or [https://en.wikipedia.org/wiki/Alzheimer%27s_disease Alzheimer's disease] are human [https://en.wikipedia.org/wiki/Degenerative_disease degenerative disease] partly due to abnormalities of the mitochondria<ref>Wang, N, S Gottesman, M C Willingham, M M Gottesman, and M R Maurizi. “A Human Mitochondrial ATP-Dependent Protease That Is Highly Homologous to Bacterial Lon Protease.” Proceedings of the National Academy of Sciences 90, no. 23 (December 1, 1993): 11247–51. https://doi.org/10.1073/pnas.90.23.11247.<br />
</ref>. In fact, Lon protease has a role in '''[https://en.wikipedia.org/wiki/Cancer cancer], [https://en.wikipedia.org/wiki/Apoptosis apoptosis] and [https://en.wikipedia.org/wiki/Ageing aging]''' because this protein is an essential part of '''developmental pathways and stress response'''.<br />
<br><br />
[https://en.wikipedia.org/wiki/Mutant Mutant] in Lon decreases the degradation capacity of proteins with abnormal conformations which lead to mitochondrial dysfunction. Mitochondrial dysfunction causes normal cells to become apoptotic, or to aberrant adaptation and selection of hypoxic phenotypes in pathological conditions like cancer<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. <br />
<br><br />
Lon expression is necessary for survival in mammals. Indeed, a [https://en.wikipedia.org/wiki/Zygosity#Homozygous homozygous] [https://en.wikipedia.org/wiki/Deletion_(genetics) deletion] of LONP1 is lethal for early embryonic<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mhttps://proteopedia.org/wiki/skins/common/images/button_extlink.pngitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. Indeed, the [https://rarediseases.info.nih.gov/diseases/1418/codas-syndrome#:~:text=Summary,-Listen&text=Codas%20syndrome%20is%20a%20multiple,Dental%2C%20Auricular%20and%20Skeletal%20anomalies.&text=To%20date%2C%20three%20affected%20children,from%20Brazil)%20have%20been%20reported. CODAS Syndrome] is a rare and multi-system developmental disorder from heterozygous or homozygous mutations in LONP1 where all the affected children were very severely impacted by their disease.<br />
<br><br />
The LONP1 gene is regulated, when the cell undergoes a '''heat shock''', [https://en.wikipedia.org/wiki/Starvation starvation] or oxidative stress the gene is '''up-regulated'''. On the contrary, Lon is '''down-regulated''' with aging, extensive [https://en.wikipedia.org/wiki/Hypoxia hypoxia], and prolonged oxidative stress. So Lon is an important factor in aging and degenerative disease. <br />
<br><br />
A [https://en.wikipedia.org/wiki/Consensus_sequence consensus] binding site of Nuclear Respiratory Factor 2 (NRF-2) is present on the region -623/+1 of the LONP1 promoter which is important for response to [https://en.wikipedia.org/wiki/Reactive_oxygen_species reactive oxygen species] related to oxidative stress. As well as the putative binding site in -2023/-1230 for [https://en.wikipedia.org/wiki/NF-%CE%BABhttps://en.wikipedia.org/wiki/NF-%CE%BAB NF-kB] in LONP1 which consolidate the role of Lon as a stress protein<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Lon Protease Preferentially Degrades Oxidized Mitochondrial Aconitase by an ATP-Stimulated Mechanism.” Nature Cell Biology 4, no. 9 (September 2002): 674–80. https://doi.org/10.1038/ncb836.</ref>. <br />
<br><br />
Research is being done to use Lon as a therapeutic target for the treatment of cancer by developing novel Lon inhibitors.</p><br />
<br />
<br />
</StructureSection><br />
<br />
== References ==<br />
<references/></div>Rose Buhlmannhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1654&diff=3342239Sandbox Reserved 16542021-01-14T17:58:20Z<p>Rose Buhlmann: </p>
<hr />
<div>{{Sandbox_Reserved_ESBS20_}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Cytoplasmic Polyadenylation Element-Binding Protein (CPEB)==<br />
[https://en.wikipedia.org/wiki/CPEB CPEB ](Cytoplasmic polyadenylation element binding protein) is present in most vertebrates and invertebrates and can activate or inhibit translation<ref>DOI 10.1016/j.tibs.2007.04.004</ref>. In human body there are 4 different isoforms of CPEB ([https://en.wikipedia.org/wiki/CPEB1 CPEB1] to CPEB4), distributed throughout body in a tissue-dependent manner and which interact differently with mRNA<ref name="publi">DOI 10.1016/j.arr.2012.03.004</ref>.<br />
CPEB protein regulates the length of the polyA tail which allows to control the translation. It binds to mRNA and in association with some factors, can act as a translational repressor or activator, depending on these factors.<br />
<br />
== Structure ==<br />
All CPEB proteins have a similar structure :<br />
* A N-terminal region which is a regulatory region with phosphorylation and dephosphorylation sites. This region is variable in length and composition.<br />
* A C-terminal region, composed of 2 recognition patterns : RRMs domains and zinc finger domains.<br />
** '''Zinc finger patterns'''<ref>DOI 10.1016/j.jmb.2013.03.009</ref><br />
<StructureSection load='2m13' size='340' side='left' caption='Zinc finger domain' scene=''><br />
</StructureSection><br />
About 54 residues with 6 cysteines and 2 histidines involved in a bond with a zinc atom, conserved for all isoforms and species. The modification of one of the eight zinc ligands destabilize the connection to the mRNA. <scene name='86/868187/Zz/3'>The domain</scene> includes :<br />
***A <scene name='86/868187/Rd_turn/1'>Rubredoxin turn</scene> (Rd turn, residues 515-520), which is stabilized by hydrogen bonds between amide and sulfure.<br />
***β-hairpin with <scene name='86/868187/B1/1'>β1</scene> (residues 525-527) and <scene name='86/868187/B2/1'>β2</scene> (residues 533-535) between which there is an helical turn stabilized by hydrogen bonds.<br />
***An <scene name='86/868187/A/1'>α1 helix</scene> (residues 538-545) which forms the second bridge between the two zinc-binding sites. The surface-exposed face of the helix has a potential for specific intermolecular interactions with nucleic acids or proteins. Therefore, it is this area that would be a platform to bind different proteins (ePAB, PARN, ...) by making hydrogen bonds. <br />
***A 3<sub>10</sub> <scene name='86/868187/310/1'> helical turn</scene> (residues 550-552).<br />
***2 zinc binding sites, the first one is composed of <scene name='86/868187/Z1/3'>Cys515, Cys518, Cys537, Cys540</scene> and the second is composed of <scene name='86/868187/Z2/2'>Cys527, Cys532, His545 and His553</scene>.<br />
** '''RRMs patterns'''<ref>DOI 10.1101/gad.241133.114</ref><br />
<StructureSection load='2MKK' size='350' side='right' caption='RNA binding to RRMs' scene=''><br />
</StructureSection><br />
RRMs are necessary and sufficient for the CPE sequence recognition on RNA. They bind to RNA with high affinity and allow the RNA to take the good position. RRM1 binds to the four first RNA nucleotides (UUUU) and RRM2 binds to the 3' adenine of CPE. The two RRMs take a V-shaped conformation, facing to each other:<br />
***<scene name='86/868187/Rmm/4'>RRM1</scene> has anti-parallel beta strands between the <scene name='86/868187/Rmm/7'>alpha helix</scene> and the <scene name='86/868187/Rmm/8'>beta4 strand</scene>.<br />
***The <scene name='86/868187/Rmm/10'>interdomain linker</scene> takes a helical turn that interacts with residues of the N-terminal extension and with <scene name='86/868187/Rmm/6'>RRM2</scene>.<br />
***<scene name='86/868187/Rmm/1'>Trp331</scene> positions RRM2 relative to RRM1 by inserting between the beta sheet and <scene name='86/868187/Rmm/9'>alpha1 helix</scene> of RRM2. <br />
***After the helical turn, the interdomain linker folds in a <scene name='86/868187/Rmm/11'>beta strand</scene> which is anti-parallel to the <scene name='86/868187/Rmm/12'>beta2 strand</scene> (RRM2). The interdomain linker is therefore a kind of joint for the relative orientation of the two RRMs.<br />
<br />
<br />
The N-terminal region of CPEB includes residues in the fourth β strand of the RRM2 domain. Within the linker region between RRM2 and ZZ domains, Leu510 shows long-range interactions with the aromatic ring of Tyr535 in the β2 strand, suggesting that there may be a close interaction between these two domains of CPEB meaning a close interaction between RRM2 and ZZ domains. Disruption of the CPEB-ZZ domain structure could affect the stability of the RRM2 domain structure through loss of the interdomain interface.<br />
<br />
== Function ==<br />
CPEB controls the balance between [https://en.wikipedia.org/wiki/Senescence senescence] and proliferation. Indeed, due to its two structural domains in its C-terminal region, it has the capacity to modify mRNA<ref name="publi" />.<br />
RRMs domains allow binding to the [https://en.wikipedia.org/wiki/Cytoplasmic_polyadenylation_element CPE] sequence of mRNA (pyrimidine rich : UUUUUAU), thus ensuring good RNA positioning and high fidelity.<br />
Zing finger domains allow binding to different proteins, which play a role in affinity but not in specificity. It's therefore its ability to recruit different proteins that will determine its action, activation or repression of translation.<br />
<br />
A specific arrangement of CPEs in mRNA can lead to the repression of the translation. In this case, the CPEB can form a dimer which could avoid the bound of the polyA polymerase complex in 2 different ways. It could prevent the association of ePAB with the polyA tail because CPEB recruits the deadenylase [https://en.wikipedia.org/wiki/Poly(A)-specific_ribonuclease PARN] which reduce the length of the polyA tail. It could disrupt the interaction between the binding factors of the translation [https://en.wikipedia.org/wiki/EIF4E eIF4E] and [https://en.wikipedia.org/wiki/EIF4G eIF4G] too, because CPEB recruits the protein Maskin which blocks eIF4G recruitment too<ref name="publi" />. This prevents the bound of the cap machinery to the mRNA and therefore inhibits the translation.<br />
<br />
On the other hand, the CPEB can activate the translation. Indeed, in the cytoplasm, there are some repressed or silenced mRNA with a short polyA tail. They can be activated by cytoplasmic polyadenylation thanks to a hormonal stimulation. This stimulation can lead to the phosphorylation of CPEB which increase its affinity with the [https://en.m.wikipedia.org/wiki/Cleavage_and_polyadenylation_specificity_factor CPSF] (Cleavage and Polyadenylation Specificity Factor) and decrease the binding between CPEB and PARN. CPSF binds to the mRNA at the sequence 3’ of the tail of the mRNA (AAUAAA) and recruits the [https://en.wikipedia.org/wiki/Polynucleotide_adenylyltransferase poly(A) polymerase] which leads to the elongation of the polyA tail and therefore to the activation of the translation<ref name="publi" />. <br />
<br />
== Diseases ==<br />
CPEB proteins play a key role in some diseases, especially in cancers. Indeed, in some humans tumors the level of CPEB 1 is lower than in healthy cells and this leads to the growth of these tumors. An overexpression of CPEB 4 can lead to tumor growth too. Some researches try to find a cancer treatment thanks to CPEB mutations<ref name="publi" />.<br />
<br />
Other diseases, like [https://en.wikipedia.org/wiki/Fragile_X_syndrome Fragile X syndrome], could be treated by regulating the expression of CPEB. Indeed, this disease is due to a mutation on [https://en.wikipedia.org/wiki/FMR1 FRM1 gene], which is bind to X chromosome. Because of this mutation, FMRP, which is a translational repressor protein, isn’t expressed. So, proteins are overexpressed and it could be the cause of some dysfunctions observed for this disease. That’s why the regulation of the level of CPEB could treat this syndrome<ref>doi: 10.1038/nm.3353</ref>.<br />
<br />
<br />
== References ==<br />
<references/></div>Rose Buhlmannhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1654&diff=3342226Sandbox Reserved 16542021-01-14T17:40:48Z<p>Rose Buhlmann: </p>
<hr />
<div>{{Sandbox_Reserved_ESBS20_}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Cytoplasmic Polyadenylation Element-Binding Protein (CPEB)==<br />
[https://en.wikipedia.org/wiki/CPEB CPEB ](Cytoplasmic polyadenylation element binding protein) is present in most vertebrates and invertebrates and can activate or inhibit translation, depending on the different factors it can bind<ref>DOI 10.1016/j.tibs.2007.04.004</ref>. In human body there are 4 different isoforms of CPEB ([https://en.wikipedia.org/wiki/CPEB1 CPEB1] to CPEB4), distributed throughout body in a tissue-dependent manner and which interact differently with mRNA<ref name="publi">DOI 10.1016/j.arr.2012.03.004</ref>.<br />
CPEB protein regulates the length of the polyA tail which allows to control the translation. It binds to mRNA and in association with some factors, can act as a translational repressor or activator, depending on these factors.<br />
<br />
== Structure ==<br />
All CPEB proteins have a similar structure :<br />
* A N-terminal region which is a regulatory region with phosphorylation and dephosphorylation sites. This region is variable in length and composition.<br />
* A C-terminal region, composed of 2 recognition patterns : RRMs domains and zinc finger domains.<br />
** '''Zinc finger patterns'''<ref>DOI 10.1016/j.jmb.2013.03.009</ref><br />
<StructureSection load='2m13' size='340' side='left' caption='Zinc finger domain' scene=''><br />
</StructureSection><br />
About 54 residues with 6 cysteines and 2 histidines involved in a bond with a zinc atom, conserved for all isoforms and species. The modification of one of the eight zinc ligands destabilize the connection to the mRNA. <scene name='86/868187/Zz/3'>The domain</scene> includes :<br />
***A <scene name='86/868187/Rd_turn/1'>Rubredoxin turn</scene> (Rd turn, residues 515-520), which is stabilized by hydrogen bonds between amide and sulfure.<br />
***β-hairpin with <scene name='86/868187/B1/1'>β1</scene> (residues 525-527) and <scene name='86/868187/B2/1'>β2</scene> (residues 533-535) between which there is an helical turn stabilized by hydrogen bonds.<br />
***An <scene name='86/868187/A/1'>α1 helix</scene> (residues 538-545) which forms the second bridge between the two zinc-binding sites. The surface-exposed face of the helix has a potential for specific intermolecular interactions with nucleic acids or proteins. Therefore, it is this area that would be a platform to bind different proteins (ePAB, PARN, ...) by making hydrogen bonds. <br />
***A 3<sub>10</sub> <scene name='86/868187/310/1'> helical turn</scene> (residues 550-552).<br />
***2 zinc binding sites, the first one is composed of <scene name='86/868187/Z1/3'>Cys515, Cys518, Cys537, Cys540</scene> and the second is composed of <scene name='86/868187/Z2/2'>Cys527, Cys532, His545 and His553</scene>.<br />
** '''RRMs patterns'''<ref>DOI 10.1101/gad.241133.114</ref><br />
<StructureSection load='2MKK' size='350' side='right' caption='RNA binding to RRMs' scene=''><br />
</StructureSection><br />
RRMs are necessary and sufficient for the CPE sequence recognition on RNA. They bind to RNA with high affinity and allow the RNA to take the good position. RRM1 binds to the four first RNA nucleotides (UUUU) and RRM2 binds to the 3' adenine of CPE. The two RRMs take a V-shaped conformation, facing to each other:<br />
***<scene name='86/868187/Rmm/4'>RRM1</scene> has anti-parallel beta strands between the <scene name='86/868187/Rmm/7'>alpha helix</scene> and the <scene name='86/868187/Rmm/8'>beta4 strand</scene>.<br />
***The <scene name='86/868187/Rmm/10'>interdomain linker</scene> takes a helical turn that interacts with residues of the N-terminal extension and with <scene name='86/868187/Rmm/6'>RRM2</scene>.<br />
***<scene name='86/868187/Rmm/1'>Trp331</scene> positions RRM2 relative to RRM1 by inserting between the beta sheet and <scene name='86/868187/Rmm/9'>alpha1 helix</scene> of RRM2. <br />
***After the helical turn, the interdomain linker folds in a <scene name='86/868187/Rmm/11'>beta strand</scene> which is anti-parallel to the <scene name='86/868187/Rmm/12'>beta2 strand</scene> (RRM2). The interdomain linker is therefore a kind of joint for the relative orientation of the two RRMs.<br />
<br />
<br />
The N-terminal region of CPEB includes residues in the fourth β strand of the RRM2 domain. Within the linker region between RRM2 and ZZ domains, Leu510 shows long-range interactions with the aromatic ring of Tyr535 in the β2 strand, suggesting that there may be a close interaction between these two domains of CPEB meaning a close interaction between RRM2 and ZZ domains. Disruption of the CPEB-ZZ domain structure could affect the stability of the RRM2 domain structure through loss of the interdomain interface.<br />
<br />
== Function ==<br />
CPEB controls the balance between [https://en.wikipedia.org/wiki/Senescence senescence] and proliferation. Indeed, due to its two structural domains in its C-terminal region, it has the capacity to modify mRNA<ref name="publi" />.<br />
RRMs domains allow binding to the [https://en.wikipedia.org/wiki/Cytoplasmic_polyadenylation_element CPE] sequence of mRNA (pyrimidine rich : UUUUUAU), thus ensuring good RNA positioning and high fidelity.<br />
Zing finger domains allow binding to different proteins, which play a role in affinity but not in specificity. It's therefore its ability to recruit different proteins that will determine its action, activation or repression of translation.<br />
<br />
A specific arrangement of CPEs in mRNA can lead to the repression of the translation. In this case, the CPEB can form a dimer which could avoid the bound of the polyA polymerase complex in 2 different ways. It could prevent the association of ePAB with the polyA tail because CPEB recruits the deadenylase [https://en.wikipedia.org/wiki/Poly(A)-specific_ribonuclease PARN] which reduce the length of the polyA tail. It could disrupt the interaction between the binding factors of the translation [https://en.wikipedia.org/wiki/EIF4E eIF4E] and [https://en.wikipedia.org/wiki/EIF4G eIF4G] too, because CPEB recruits the protein Maskin which blocks eIF4G recruitment too<ref name="publi" />. This prevents the bound of the cap machinery to the mRNA and therefore inhibits the translation.<br />
<br />
On the other hand, the CPEB can activate the translation. Indeed, in the cytoplasm, there are some repressed or silenced mRNA with a short polyA tail. They can be activated by cytoplasmic polyadenylation thanks to a hormonal stimulation. This stimulation can lead to the phosphorylation of CPEB which increase its affinity with the [https://en.m.wikipedia.org/wiki/Cleavage_and_polyadenylation_specificity_factor CPSF] (Cleavage and Polyadenylation Specificity Factor) and decrease the binding between CPEB and PARN. CPSF binds to the mRNA at the sequence 3’ of the tail of the mRNA (AAUAAA) and recruits the [https://en.wikipedia.org/wiki/Polynucleotide_adenylyltransferase poly(A) polymerase] which leads to the elongation of the polyA tail and therefore to the activation of the translation<ref name="publi" />. <br />
<br />
== Diseases ==<br />
CPEB proteins play a key role in some diseases, especially in cancers. Indeed, in some humans tumors the level of CPEB 1 is lower than in healthy cells and this leads to the growth of these tumors. An overexpression of CPEB 4 can lead to tumor growth too. Some researches try to find a cancer treatment thanks to CPEB mutations<ref name="publi" />.<br />
<br />
Other diseases, like [https://en.wikipedia.org/wiki/Fragile_X_syndrome Fragile X syndrome], could be treated by regulating the expression of CPEB. Indeed, this disease is due to a mutation on [https://en.wikipedia.org/wiki/FMR1 FRM1 gene], which is bind to X chromosome. Because of this mutation, FMRP, which is a translational repressor protein, isn’t expressed. So, proteins are overexpressed and it could be the cause of some dysfunctions observed for this disease. That’s why the regulation of the level of CPEB could treat this syndrome<ref>doi: 10.1038/nm.3353</ref>.<br />
<br />
<br />
== References ==<br />
<references/></div>Rose Buhlmannhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1654&diff=3342217Sandbox Reserved 16542021-01-14T17:31:13Z<p>Rose Buhlmann: </p>
<hr />
<div>{{Sandbox_Reserved_ESBS20_}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Cytoplasmic Polyadenylation Element-Binding Protein (CPEB)==<br />
[https://en.wikipedia.org/wiki/CPEB CPEB ](Cytoplasmic polyadenylation element binding protein) is present in most vertebrates and invertebrates and can activate or inhibit translation, depending on the different factors it can bind<ref>DOI 10.1016/j.tibs.2007.04.004</ref>. In human body there are 4 different isoforms of CPEB ([https://en.wikipedia.org/wiki/CPEB1 CPEB1] to CPEB4), distributed throughout body in a tissue-dependent manner and which interact differently with mRNA<ref name="publi">DOI 10.1016/j.arr.2012.03.004</ref>.<br />
CPEB protein regulates the length of the polyA tail which allows to control the translation. It binds to mRNA and in association with some factors, can act as a translational repressor or activator, depending on these factors.<br />
<br />
== Structure ==<br />
All CPEB proteins have a similar structure :<br />
* A N-terminal region which is a regulatory region with phosphorylation and dephosphorylation sites. This region is variable in length and composition.<br />
* A C-terminal region, composed of 2 recognition patterns : RRMs domains and zinc finger domains.<br />
** '''Zinc finger patterns'''<ref>DOI 10.1016/j.jmb.2013.03.009</ref><br />
<StructureSection load='2m13' size='340' side='left' caption='Zinc finger domain' scene=''><br />
</StructureSection><br />
About 54 residues with 6 cysteines and 2 histidines involved in a bond with a zinc atom, conserved for all isoforms and species. The modification of one of the eight zinc ligands destabilize the connection to the mRNA. <scene name='86/868187/Zz/3'>The domain</scene> includes :<br />
***A <scene name='86/868187/Rd_turn/1'>Rubredoxin turn</scene> (Rd turn, residues 515-520), which is stabilized by hydrogen bonds between amide and sulfure.<br />
***β-hairpin with <scene name='86/868187/B1/1'>β1</scene> (residues 525-527) and <scene name='86/868187/B2/1'>β2</scene> (residues 533-535) between which there is an helical turn stabilized by hydrogen bonds.<br />
***An <scene name='86/868187/A/1'>α1 helix</scene> (residues 538-545) which forms the second bridge between the two zinc-binding sites. The surface-exposed face of the helix has a potential for specific intermolecular interactions with nucleic acids or proteins. Therefore, it is this area that would be a platform to bind different proteins (ePAB, PARN, ...) by making hydrogen bonds. <br />
***A 3<sub>10</sub> <scene name='86/868187/310/1'> helical turn</scene> (residues 550-552).<br />
***2 zinc binding sites, the first one is composed of <scene name='86/868187/Z1/3'>Cys515, Cys518, Cys537, Cys540</scene> and the second is composed of <scene name='86/868187/Z2/2'>Cys527, Cys532, His545 and His553</scene>.<br />
** '''RRMs patterns'''<ref>DOI 10.1101/gad.241133.114</ref><br />
<StructureSection load='2MKK' size='350' side='right' caption='RNA binding to RRMs' scene=''><br />
</StructureSection><br />
RRMs are necessary and sufficient for the CPE sequence recognition on RNA. They bind to RNA with high affinity and allow the RNA to take the good position. RRM1 binds to the four first RNA nucleotides (UUUU) and RRM2 binds to the 3' adenine of CPE. The two RRMs take a V-shaped conformation, facing to each other:<br />
***<scene name='86/868187/Rmm/4'>RRM1</scene> has anti-parallel beta strands between the <scene name='86/868187/Rmm/7'>alpha helix</scene> and the <scene name='86/868187/Rmm/8'>beta4 strand</scene>.<br />
***The <scene name='86/868187/Rmm/10'>interdomain linker</scene> takes a helical turn that interacts with residues of the N-terminal extension and with <scene name='86/868187/Rmm/6'>RRM2</scene>.<br />
***<scene name='86/868187/Rmm/1'>Trp331</scene> positions RRM2 relative to RRM1 by inserting between the beta sheet and <scene name='86/868187/Rmm/9'>alpha1 helix</scene> of RRM2. <br />
***After the helical turn, the interdomain linker folds in a <scene name='86/868187/Rmm/11'>beta strand</scene> which is anti-parallel to the <scene name='86/868187/Rmm/12'>beta2 strand</scene> (RRM2). The interdomain linker is therefore a kind of joint for the relative orientation of the two RRMs.<br />
<br />
<br />
The N-terminal region of CPEB includes residues in the fourth β strand of the RRM2 domain. Within the linker region between RRM2 and ZZ domains, Leu510 shows long-range interactions with the aromatic ring of Tyr535 in the β2 strand, suggesting that there may be a close interaction between these two domains of CPEB meaning a close interaction between RRM2 and ZZ domains. Disruption of the CPEB-ZZ domain structure could affect the stability of the RRM2 domain structure through loss of the interdomain interface.<br />
<br />
== Function ==<br />
CPEB controls the balance between [https://en.wikipedia.org/wiki/Senescence senescence] and proliferation. Indeed, due to its two structural domains in its C-terminal region, it has the capacity to modify mRNA<ref name="publi" />.<br />
RRMs domains allow binding to the [https://en.wikipedia.org/wiki/Cytoplasmic_polyadenylation_element CPE] sequence of mRNA (pyrimidine rich : UUUUUAU), thus ensuring good RNA positioning and high fidelity.<br />
Zing finger domains allow binding to different proteins, which play a role in affinity but not in specificity. It's therefore its ability to recruit different proteins that will determine its action, activation or repression of translation.<br />
<br />
A specific arrangement of CPEs in mRNA can lead to the repression of the translation. In this case, the CPEB can form a dimer which could avoid the bound of the polyA polymerase complex in 2 different ways. It could prevent the association of ePAB with the polyA tail because CPEB recruits the deadenylase [https://en.wikipedia.org/wiki/Poly(A)-specific_ribonuclease PARN] which reduce the length of the polyA tail. It could disrupt the interaction between the binding factors of the translation [https://en.wikipedia.org/wiki/EIF4E eIF4E] and [https://en.wikipedia.org/wiki/EIF4G eIF4G] too, because CPEB recruits the protein Maskin which blocks eIF4G recruitment too<ref name="publi" />. This prevents the bound of the cap machinery to the mRNA and therefore inhibits the translation.<br />
<br />
On the other hand, the CPEB can activate the translation. Indeed, in the cytoplasm, there are some repressed or silenced mRNA with a short polyA tail. They can be activated by cytoplasmic polyadenylation thanks to a hormonal stimulation. This stimulation can lead to the phosphorylation of CPEB which increase its affinity with the [https://en.m.wikipedia.org/wiki/Cleavage_and_polyadenylation_specificity_factor CPSF] (Cleavage and Polyadenylation Specificity Factor) and decrease the binding between CPEB and PARN. CPSF binds to the mRNA at the sequence 3’ of the tail of the mRNA (AAUAAA) and recruits the [https://en.wikipedia.org/wiki/Polynucleotide_adenylyltransferase poly(A) polymerase] which leads to the elongation of the polyA tail and therefore to the activation of the translation<ref name="publi" />. <br />
<br />
== Diseases ==<br />
CPEB proteins play a key role in some diseases, especially in cancers. Indeed, in some humans tumors the level of CPEB 1 is lower than in healthy cells and this leads to the growth of these tumors. An overexpression of CPEB 4 can lead to tumor growth too. Some researches try to find a cancer treatment thanks to CPEB mutations<ref name="publi" />.<br />
<br />
Other diseases, like [https://en.wikipedia.org/wiki/Fragile_X_syndrome Fragile X syndrome], could be treated by regulating the expression of CPEB. Indeed, this disease is due to a mutation on [https://en.wikipedia.org/wiki/FMR1 FRM1 gene], which is bind to X chromosome. Because of this mutation, FMRP, which is a translational repressor protein, isn’t expressed. So, proteins are overexpressed and it could be the cause of some dysfunctions observed for this disease. That’s why the regulation of the level of CPEB could treat this syndrome.<br />
<br />
<br />
== References ==<br />
<references/></div>Rose Buhlmannhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1654&diff=3342212Sandbox Reserved 16542021-01-14T17:24:06Z<p>Rose Buhlmann: </p>
<hr />
<div>{{Sandbox_Reserved_ESBS20_}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Cytoplasmic Polyadenylation Element-Binding Protein (CPEB)==<br />
[https://en.wikipedia.org/wiki/CPEB CPEB ](Cytoplasmic polyadenylation element binding protein) is present in most vertebrates and invertebrates and can activate or inhibit translation, depending on the different factors it can bind<ref>DOI 10.1016/j.tibs.2007.04.004</ref>. In human body there are 4 different isoforms of CPEB ([https://en.wikipedia.org/wiki/CPEB1 CPEB1] to CPEB4), distributed throughout body in a tissue-dependent manner and which interact differently with mRNA<ref name="publi">DOI 10.1016/j.arr.2012.03.004</ref>.<br />
CPEB protein regulates the length of the polyA tail which allows to control the translation. It binds to mRNA and in association with some factors, can act as a translational repressor or activator, depending on these factors.<br />
<br />
== Structure ==<br />
All CPEB proteins have a similar structure :<br />
* A N-terminal region which is a regulatory region with phosphorylation and dephosphorylation sites. This region is variable in length and composition.<br />
* A C-terminal region, composed of 2 recognition patterns : RRMs domains and zinc finger domains.<br />
** '''Zinc finger patterns'''<ref>DOI 10.1016/j.jmb.2013.03.009</ref><br />
<StructureSection load='2m13' size='340' side='left' caption='Zinc finger domain' scene=''><br />
</StructureSection><br />
About 54 residues with 6 cysteines and 2 histidines involved in a bond with a zinc atom, conserved for all isoforms and species. The modification of one of the eight zinc ligands destabilize the connection to the mRNA. <scene name='86/868187/Zz/3'>The domain</scene> includes :<br />
***A <scene name='86/868187/Rd_turn/1'>Rubredoxin turn</scene> (Rd turn, residues 515-520), which is stabilized by hydrogen bonds between amide and sulfure.<br />
***β-hairpin with <scene name='86/868187/B1/1'>β1</scene> (residues 525-527) and <scene name='86/868187/B2/1'>β2</scene> (residues 533-535) between which there is an helical turn stabilized by hydrogen bonds.<br />
***An <scene name='86/868187/A/1'>α1 helix</scene> (residues 538-545) which forms the second bridge between the two zinc-binding sites. The surface-exposed face of the helix has a potential for specific intermolecular interactions with nucleic acids or proteins. Therefore, it is this area that would be a platform to bind different proteins (ePAB, PARN, ...) by making hydrogen bonds. <br />
***A 3<sub>10</sub> <scene name='86/868187/310/1'> helical turn</scene> (residues 550-552).<br />
***2 zinc binding sites, the first one is composed of <scene name='86/868187/Z1/3'>Cys515, Cys518, Cys537, Cys540</scene> and the second is composed of <scene name='86/868187/Z2/2'>Cys527, Cys532, His545 and His553</scene>.<br />
** '''RRMs patterns'''<ref>DOI 10.1101/gad.241133.114</ref><br />
<StructureSection load='2MKK' size='350' side='right' caption='RNA binding to RRMs' scene=''><br />
</StructureSection><br />
RRMs are necessary and sufficient for the CPE sequence recognition on RNA. They bind to RNA with high affinity and allow the RNA to take the good position. RRM1 binds to the four first RNA nucleotides (UUUU) and RRM2 binds to the 3' adenine of CPE. The two RRMs take a V-shaped conformation, facing to each other:<br />
***<scene name='86/868187/Rmm/4'>RRM1</scene> has anti-parallel beta strands between the <scene name='86/868187/Rmm/7'>alpha helix</scene> and the <scene name='86/868187/Rmm/8'>beta4 strand</scene>.<br />
***The <scene name='86/868187/Rmm/10'>interdomain linker</scene> takes a helical turn that interacts with residues of the N-terminal extension and with <scene name='86/868187/Rmm/6'>RRM2</scene>.<br />
***<scene name='86/868187/Rmm/1'>Trp331</scene> positions RRM2 relative to RRM1 by inserting between the beta sheet and <scene name='86/868187/Rmm/9'>alpha1 helix</scene> of RRM2. <br />
***After the helical turn, the interdomain linker folds in a <scene name='86/868187/Rmm/11'>beta strand</scene> which is anti-parallel to the <scene name='86/868187/Rmm/12'>beta2 strand</scene> (RRM2). The interdomain linker is therefore a kind of joint for the relative orientation of the two RRMs.<br />
<br />
<br />
The N-terminal region of CPEB includes residues in the fourth β strand of the RRM2 domain. Within the linker region between RRM2 and ZZ domains, Leu510 shows long-range interactions with the aromatic ring of Tyr535 in the β2 strand, suggesting that there may be a close interaction between these two domains of CPEB meaning a close interaction between RRM2 and ZZ domains. Disruption of the CPEB-ZZ domain structure could affect the stability of the RRM2 domain structure through loss of the interdomain interface.<br />
<br />
== Function ==<br />
CPEB controls the balance between [https://en.wikipedia.org/wiki/Senescence senescence] and proliferation. Indeed, due to its two structural domains in its C-terminal region, it has the capacity to modify mRNA<ref name="publi" />.<br />
RRMs domains allow binding to the [https://en.wikipedia.org/wiki/Cytoplasmic_polyadenylation_element CPE] sequence of mRNA (pyrimidine rich : UUUUUAU), thus ensuring good RNA positioning and high fidelity.<br />
Zing finger domains allow binding to different proteins, which play a role in affinity but not in specificity. It's therefore its ability to recruit different proteins that will determine its action, activation or repression of translation.<br />
<br />
A specific arrangement of CPEs in mRNA can lead to the repression of the translation. In this case, the CPEB can form a dimer which could avoid the bound of the polyA polymerase complex in 2 different ways. It could prevent the association of ePAB with the polyA tail because CPEB recruits the deadenylase [https://en.wikipedia.org/wiki/Poly(A)-specific_ribonuclease PARN] which reduce the length of the polyA tail. It could disrupt the interaction between the binding factors of the translation [https://en.wikipedia.org/wiki/EIF4E eIF4E] and [https://en.wikipedia.org/wiki/EIF4G eIF4G] too, because CPEB recruits the protein Maskin which blocks eIF4G recruitment too<ref name="publi" />. This prevents the bound of the cap machinery to the mRNA and therefore inhibits the translation.<br />
<br />
On the other hand, the CPEB can activate the translation. Indeed, in the cytoplasm, there are some repressed or silenced mRNA with a short polyA tail. They can be activated by cytoplasmic polyadenylation thanks to a hormonal stimulation. This stimulation can lead to the phosphorylation of CPEB which increase its affinity with the [https://en.m.wikipedia.org/wiki/Cleavage_and_polyadenylation_specificity_factor CPSF] (Cleavage and Polyadenylation Specificity Factor) and decrease the binding between CPEB and PARN. CPSF binds to the mRNA at the sequence 3’ of the tail of the mRNA (AAUAAA) and recruits the [https://en.wikipedia.org/wiki/Polynucleotide_adenylyltransferase poly(A) polymerase] which leads to the elongation of the polyA tail and therefore to the activation of the translation<ref name="publi" />. <br />
<br />
== Diseases ==<br />
CPEB proteins play a key role in some diseases, especially in cancers. Indeed, in some humans tumors the level of CPEB 1 is lower than in healthy cells and this leads to the growth of these tumors. An overexpression of CPEB 4 can lead to tumor growth too. Some researches try to find a cancer treatment thanks to CPEB mutations.<br />
<br />
Other diseases, like [https://en.wikipedia.org/wiki/Fragile_X_syndrome Fragile X syndrome], could be treated by regulating the expression of CPEB. Indeed, this disease is due to a mutation on [https://en.wikipedia.org/wiki/FMR1 FRM1 gene], which is bind to X chromosome. Because of this mutation, FMRP, which is a translational repressor protein, isn’t expressed. So, proteins are overexpressed and it could be the cause of some dysfunctions observed for this disease. That’s why the regulation of the level of CPEB could treat this syndrome.<br />
<br />
<br />
== References ==<br />
<references/></div>Rose Buhlmannhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1654&diff=3342209Sandbox Reserved 16542021-01-14T17:21:52Z<p>Rose Buhlmann: </p>
<hr />
<div>{{Sandbox_Reserved_ESBS20_}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Cytoplasmic Polyadenylation Element-Binding Protein (CPEB)==<br />
[https://en.wikipedia.org/wiki/CPEB CPEB ](Cytoplasmic polyadenylation element binding protein) is present in most vertebrates and invertebrates and can activate or inhibit translation, depending on the different factors it can bind<ref>DOI 10.1016/j.tibs.2007.04.004</ref>. In human body there are 4 different isoforms of CPEB ([https://en.wikipedia.org/wiki/CPEB1 CPEB1] to CPEB4), distributed throughout body in a tissue-dependent manner and which interact differently with mRNA<ref name="publi">DOI 10.1016/j.arr.2012.03.004</ref>.<br />
CPEB protein regulates the length of the polyA tail which allows to control the translation. It binds to mRNA and in association with some factors, can act as a translational repressor or activator, depending on these factors.<br />
<br />
== Structure ==<br />
All CPEB proteins have a similar structure :<br />
* A N-terminal region which is a regulatory region with phosphorylation and dephosphorylation sites. This region is variable in length and composition.<br />
* A C-terminal region, composed of 2 recognition patterns : RRMs domains and zinc finger domains.<br />
** '''Zinc finger patterns'''<ref>DOI 10.1016/j.jmb.2013.03.009</ref><br />
<StructureSection load='2m13' size='340' side='left' caption='Zinc finger domain' scene=''><br />
</StructureSection><br />
About 54 residues with 6 cysteines and 2 histidines involved in a bond with a zinc atom, conserved for all isoforms and species. The modification of one of the eight zinc ligands destabilize the connection to the mRNA. <scene name='86/868187/Zz/3'>The domain</scene> includes :<br />
***A <scene name='86/868187/Rd_turn/1'>Rubredoxin turn</scene> (Rd turn, residues 515-520), which is stabilized by hydrogen bonds between amide and sulfure.<br />
***β-hairpin with <scene name='86/868187/B1/1'>β1</scene> (residues 525-527) and <scene name='86/868187/B2/1'>β2</scene> (residues 533-535) between which there is an helical turn stabilized by hydrogen bonds.<br />
***An <scene name='86/868187/A/1'>α1 helix</scene> (residues 538-545) which forms the second bridge between the two zinc-binding sites. The surface-exposed face of the helix has a potential for specific intermolecular interactions with nucleic acids or proteins. Therefore, it is this area that would be a platform to bind different proteins (ePAB, PARN, ...) by making hydrogen bonds. <br />
***A 3<sub>10</sub> <scene name='86/868187/310/1'> helical turn</scene> (residues 550-552).<br />
***2 zinc binding sites, the first one is composed of <scene name='86/868187/Z1/3'>Cys515, Cys518, Cys537, Cys540</scene> and the second is composed of <scene name='86/868187/Z2/2'>Cys527, Cys532, His545 and His553</scene>.<br />
** '''RRMs patterns'''<ref>DOI 10.1101/gad.241133.114</ref><br />
<StructureSection load='2MKK' size='350' side='right' caption='RNA binding to RRMs' scene=''><br />
</StructureSection><br />
RRMs are necessary and sufficient for the CPE sequence recognition on RNA. They bind to RNA with high affinity and allow the RNA to take the good position. RRM1 binds to the four first RNA nucleotides (UUUU) and RRM2 binds to the 3' adenine of CPE. The two RRMs take a V-shaped conformation, facing to each other:<br />
***<scene name='86/868187/Rmm/4'>RRM1</scene> has anti-parallel beta strands between the <scene name='86/868187/Rmm/7'>alpha helix</scene> and the <scene name='86/868187/Rmm/8'>beta4 strand</scene>.<br />
***The <scene name='86/868187/Rmm/10'>interdomain linker</scene> takes a helical turn that interacts with residues of the N-terminal extension and with <scene name='86/868187/Rmm/6'>RRM2</scene>.<br />
***<scene name='86/868187/Rmm/1'>Trp331</scene> positions RRM2 relative to RRM1 by inserting between the beta sheet and <scene name='86/868187/Rmm/9'>alpha1 helix</scene> of RRM2. <br />
***After the helical turn, the interdomain linker folds in a <scene name='86/868187/Rmm/11'>beta strand</scene> which is anti-parallel to the <scene name='86/868187/Rmm/12'>beta2 strand</scene> (RRM2). The interdomain linker is therefore a kind of joint for the relative orientation of the two RRMs.<br />
<br />
<br />
The N-terminal region of CPEB includes residues in the fourth β strand of the RRM2 domain. Within the linker region between RRM2 and ZZ domains, Leu510 shows long-range interactions with the aromatic ring of Tyr535 in the β2 strand, suggesting that there may be a close interaction between these two domains of CPEB meaning a close interaction between RRM2 and ZZ domains. Disruption of the CPEB-ZZ domain structure could affect the stability of the RRM2 domain structure through loss of the interdomain interface.<br />
<br />
== Function ==<br />
CPEB controls the balance between [https://en.wikipedia.org/wiki/Senescence senescence] and proliferation. Indeed, due to its two structural domains in its C-terminal region, it has the capacity to modify mRNA<ref name="publi" />.<br />
RRMs domains allow binding to the [https://en.wikipedia.org/wiki/Cytoplasmic_polyadenylation_element CPE] sequence of mRNA (pyrimidine rich : UUUUUAU), thus ensuring good RNA positioning and high fidelity.<br />
Zing finger domains allow binding to different proteins, which play a role in affinity but not in specificity. It's therefore its ability to recruit different proteins that will determine its action, activation or repression of translation.<br />
<br />
A specific arrangement of CPEs in mRNA can lead to the repression of the translation. In this case, the CPEB can form a dimer which could avoid the bound of the polyA polymerase complex in 2 different ways. It could prevent the association of ePAB with the polyA tail because CPEB recruits the deadenylase [https://en.wikipedia.org/wiki/Poly(A)-specific_ribonuclease PARN] which reduce the length of the polyA tail. It could disrupt the interaction between the binding factors of the translation [https://en.wikipedia.org/wiki/EIF4E eIF4E] and [https://en.wikipedia.org/wiki/EIF4G eIF4G] too, because CPEB recruits the protein Maskin which blocks eIF4G recruitment too<ref name="publi" />. This prevents the bound of the cap machinery to the mRNA and therefore inhibits the translation.<br />
<br />
On the other hand, the CPEB can activate the translation. Indeed, in the cytoplasm, there are some repressed or silenced mRNA with a short polyA tail. They can be activated by cytoplasmic polyadenylation thanks to a hormonal stimulation. This stimulation can lead to the phosphorylation of CPEB which increase its affinity with the [https://en.m.wikipedia.org/wiki/Cleavage_and_polyadenylation_specificity_factor CPSF] (Cleavage and Polyadenylation Specificity Factor) and decrease the binding between CPEB and PARN. CPSF binds to the mRNA at the sequence 3’ of the tail of the mRNA (AAUAAA) and recruits the [https://en.wikipedia.org/wiki/Polynucleotide_adenylyltransferase poly(A) polymerase] which leads to the elongation of the polyA tail and therefore to the activation of the translation<ref name="publi" />. <br />
<br />
== Diseases ==<br />
CPEB proteins play a key role in some diseases, especially in cancers. Indeed, in some humans tumors the level of CPEB 1 is lower than in healthy cells and this leads to the growth of these tumors. An overexpression of CPEB 4 can lead to tumor growth too. Some researches try to find a cancer treatment thanks to CPEB mutations.<br />
<br />
Other diseases, like Fragile X syndrome, could be treated by regulating the expression of CPEB. Indeed, this disease is due to a mutation on FRM1 gene, which is bind to X chromosome. Because of this mutation, FMRP, which is a translational repressor protein, isn’t expressed. So, proteins are overexpressed and it could be the cause of some dysfunctions observed for this disease. That’s why the regulation of the level of CPEB could treat this syndrome.<br />
<br />
<br />
== References ==<br />
<references/></div>Rose Buhlmannhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1644&diff=3342192Sandbox Reserved 16442021-01-14T17:08:08Z<p>Rose Buhlmann: </p>
<hr />
<div>{{Sandbox_Reserved_ESBS20_}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==2x36 - Structure of the proteolytic domain of the <scene name='86/868177/Structure_hmlon_protease/1'>Human Mitochondrial Lon protease</scene>==<br />
<StructureSection load='2x36' size='340' side='right' caption='Structure of the Human Mitochondrial Lon protease' scene=''><br />
<br />
<p align="justify">'''2x36''' is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. This domain belongs to the [https://en.wikipedia.org/wiki/Lon_protease_family Lon protease family]. <br />
<br><br />
[https://en.wikipedia.org/wiki/Mitochondrion Mitochondrial] Lon [https://en.wikipedia.org/wiki/Protease protease] is an '''ATP-dependent serine protease''' involved '''in the selective degradation of abnormal proteins'''. [https://en.wikipedia.org/wiki/LONP1 LONP1] situated on chromosome 19 is the nuclear gene encoding mitochondrial Lon protein. The single species of [https://en.wikipedia.org/wiki/Messenger_RNA mRNA] of this protein is found in the mitochondrial matrix. This protein from human tissues has a molecular mass of 100 [https://en.wikipedia.org/wiki/Dalton_(unit) kDA].</p><br />
<br><br />
== Function ==<br />
<br />
<p align="justify">The mitochondrial Lon protease is an important regulator of mitochondrial [https://en.wikipedia.org/wiki/Metabolism metabolism] including the maintenance and repair of mitochondrial [https://en.wikipedia.org/wiki/DNA DNA]. This protein is also essential for homeostasis of mitochondria, and by regulating some regulatory proteins which have a short life or damaged proteins. <br />
<br><br />
<br><br />
Lon protease has three main roles<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. <br />
This protein is able to do a '''[https://en.wikipedia.org/wiki/Proteolysis proteolytic] digestion''' of oxidized proteins which allows the renewal of essential mitochondrial enzymes such as [https://en.wikipedia.org/wiki/Aconitase aconitase] or [https://en.wikipedia.org/wiki/TFAM Mitochondrial transcription factor A].<br />
Lon protease is involved in [https://en.wikipedia.org/wiki/Mitochondrial_DNA mtDNA] [https://en.wikipedia.org/wiki/DNA_replication replication] and [https://en.wikipedia.org/w/index.php?title=Mitogenesis&redirect=no mitogenesis] by being a '''mitochondrial [https://en.wikipedia.org/wiki/DNA-binding_protein DNA-bing protein]'''. Human Lon and mtDNA associate at the level of their at least 4 contiguous [https://en.wikipedia.org/wiki/Guanine guanine] sequence and form a [https://en.wikipedia.org/wiki/G-quadruplex G-quadruplex]<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. This G-rich region is the control region for mtDNA replication and transcription<ref>Lu, Bin. “Mitochondrial Lon Protease and Cancer.” Advances in Experimental Medicine and Biology 1038 (2017): 173–82. https://doi.org/10.1007/978-981-10-6674-0_12.</ref>. <br />
<br><br />
Mitochondrial Lon protease interacts with '''[https://en.wikipedia.org/wiki/Chaperone_(protein) protein chaperone]''', notably [https://en.wikipedia.org/wiki/Chaperonin HSP60]-[https://en.wikipedia.org/wiki/Hsp70 Hsp70] complex to protect cell from apoptosis under environmental stress<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>.<br />
<br><br />
The mitochondrial Lon protease is essentially found in the cytoplasmic of mitochondria because [https://en.wikipedia.org/wiki/Amino_acid amino-acid] has a potential mitochondrial targetting presequences<ref>García-Nafría, Javier, Gabriela Ondrovičová, Elena Blagova, Vladimir M Levdikov, Jacob A Bauer, Carolyn K Suzuki, Eva Kutejová, Anthony J Wilkinson, and Keith S Wilson. “Structure of the Catalytic Domain of the Human Mitochondrial Lon Protease: Proposed Relation of Oligomer Formation and Activity.” Protein Science : A Publication of the Protein Society 19, no. 5 (May 2010): 987–99. https://doi.org/10.1002/pro.376.</ref>.<br />
<br><br />
Lon Human protease alternates between cycles of '''being bound to the mitochondrial genome''' and '''being free into the mitochondrial cytoplasm''' where it can degrade abnormal proteins coming from damaged proteins, errors in the synthesis, or [https://en.wikipedia.org/wiki/Protein_folding misfolded] of multimeric proteins. Its inactive conformation prevents uncontrolled proteolysis. <br />
To achieve proteolytic cleavage, the Lon protein has to form a hexamer. <br />
Lon protease has also a role in mtDNA quality control by permits oxidative mitochondrial DNA damage. Sensitivities of H2O2-induced mtDNA damage depend on the proportion of LON<ref>Lu, Bin. “Mitochondrial Lon Protease and Cancer.” Advances in Experimental Medicine and Biology 1038 (2017): 173–82. https://doi.org/10.1007/978-981-10-6674-0_12.</ref>. <br />
Other ATP-dependent proteases are found in eukaryotic cells and organelles like [https://en.wikipedia.org/wiki/Proteasome_endopeptidase_complex 26S protease] which uses [https://en.wikipedia.org/wiki/ATP_hydrolysis ATP hydrolysis] for conjugation or ubiquitin for example.</p><br />
<br><br />
<br />
== General structure ==<br />
<br />
<p align="justify">Lon proteins are grouped into two families, '''LonA''' and '''LonB'''. The human protein LonP1 is part of the LonA proteins <ref>« The N-terminal domain plays a crucial role in the structure of a full-length human mitochondrial Lon protease | Scientific Reports ». Consulté le 13 janvier 2021. https://www.nature.com/articles/srep33631.<br />
</ref>. This protein has three isoforms obtained by [https://en.wikipedia.org/wiki/Alternative_splicing alternative splicing] of the portion of DNA coding for this protein <ref>He, Lihong, Dongyang Luo, Fan Yang, Chunhao Li, Xuegong Zhang, Haiteng Deng, et Jing-Ren Zhang. « Multiple domains of bacterial and human Lon proteases define substrate selectivity ». Emerging Microbes & Infections 7 (17 août 2018). https://doi.org/10.1038/s41426-018-0148-4.<br />
</ref>.<br />
Globally there is a great diversity of Lon proteins, but they are all organised in an oligomeric ring structure, mostly hexameric structure with identical subunits.<br />
Lon proteins are therefore an hexameric chambered [https://en.wikipedia.org/wiki/Protease protease] complex. (This structure is similar with yeast [https://www.yeastgenome.org/locus/S000000118 Pim1] )<br />
The six Lon monomers are forming three pairs of legs owned by the N-terminal domain of the protein. This structure is emerging of the protein as a trimer of dimers <ref>Kutejová, Eva. « Mitochondrial Lon protease-unique structure and essential function in mammalian cells ». Integrative Cancer Science and Therapeutics 5, nᵒ 6 (2018). https://doi.org/10.15761/ICST.1000296.<br />
</ref>.<br />
<br><br />
Like many proteins, Lon is a '''flexible''' peptide which has different '''three-dimensional conformations'''. The protein can therefore pass from one conformation to another by hydrolysis of [https://biologydictionary.net/atp/ ATP]<ref>Voos, Wolfgang, et Karen Pollecker. « The Mitochondrial Lon Protease: Novel Functions off the Beaten Track? » Biomolecules 10, nᵒ 2 (7 février 2020). https://doi.org/10.3390/biom10020253.<br />
</ref>.<br />
With these conformational changes, the [https://en.wikipedia.org/wiki/Active_site '''active sites'''] of the Lon protein are protected from the external environment in the oligomeric complex that forms the '''degradation chamber'''.<br />
This form of degradation chamber is also found in bacteria, plants, fungi and metazoan, the similarities with bacteria are most probably due to the [https://en.wikipedia.org/wiki/Symbiogenesis endosymbiotic theory].<br />
<br><br />
<br><br />
This protein has a [https://en.wikipedia.org/wiki/Proteolysis '''proteolytic'''] and [https://en.wikipedia.org/wiki/Chaperone_(protein) '''chaperone''']-like activity, it cannot unfold aggregated proteins, but can participate in the assembling of some complexes). These two enzymatic activities are separated on two polypeptide chains forming a complex or two separate domains on the same polypeptide chain.<br />
<br><br />
The Lon protein has three main distinct domains: the first, the '''N-terminal''' domain, is specialised in '''substrate binding''' and [https://en.wikipedia.org/wiki/Oligomer '''oligomerization''']. The second, called the '''AAA+ domain''' (or A domain) corresponds to the fixation and hydrolysis site of the [https://biologydictionary.net/atp/ATP ATP]. Finally, the third domain located at the '''C-terminal''' is an active serine site leading to '''substrate degradation'''. This is a [https://en.wikipedia.org/wiki/Proteolysis '''proteolytic'''] domain, called domain P <ref>He, Lihong, Dongyang Luo, Fan Yang, Chunhao Li, Xuegong Zhang, Haiteng Deng, et Jing-Ren Zhang. « Multiple domains of bacterial and human Lon proteases define substrate selectivity ». Emerging Microbes & Infections 7 (17 août 2018). https://doi.org/10.1038/s41426-018-0148-4.<br />
</ref>.<br />
<br><br />
Mammalian Lon protein only interacts with '''single-stranded DNA''' (ssDNA) but not dsDNA. There are therefore special sequences for interaction with '''G-rich DNA''' as well as RNA. In addition, the binding of a substrate to the protein stimulates the interaction with the DNA.<br />
[https://en.wikipedia.org/wiki/Mitochondrial_DNA mtDNA] binds to the Lon protein with different affinities depending on the state of the cell and the type of cell meeting the following four parameters <ref>Lu, Bin, Swati Yadav, Parul G. Shah, Tong Liu, Bin Tian, Sebastian Pukszta, Nerissa Villaluna, et al. « Roles for the Human ATP-Dependent Lon Protease in Mitochondrial DNA Maintenance ». Journal of Biological Chemistry 282, nᵒ 24 (15 juin 2007): 17363‑74. https://doi.org/10.1074/jbc.M611540200.<br />
</ref>: <br />
<br><br />
- the single stranding state of mtDNA<br />
<br><br />
- the bioavailability of the mtDNA binding sites<br />
<br><br />
- the affinity of the protein for a given DNA sequence<br />
<br><br />
- the total number of high and low affinity Lon binding sites present</p><br />
<br />
<br />
<br />
<br />
== Structural highlights ==<br />
<br />
From hLon main three domains, the ATPase domain and the C-terminal active site are those which confer to the protein its function.<br />
<br />
The [https://en.wikipedia.org/wiki/ATPase ATPase] domain enables after the '''consumption of an ATP molecule''' to get the required energy for the active site to [https://en.wikipedia.org/wiki/Hydrolysis hydrolyze] protein substrates. It has been demonstrated that the presence of ADP induces a conformational change to obtain an '''asymmetric hexametric ring'''. As a result, the catalytic site reaches its '''open state''' where the protein substrate can bind. ATP most likely replaces ADP from the ATPase domain to cut off the next substrate. In presence of AMP the hexametric ring takes a '''closed conformation''' state suggesting that until either ATP or ADP is present in the environment, hLon has the capacity to perform its catalytic activity<ref>PMID: 27632940</ref>. <br />
<br />
<br />
== Evolutionary conservation ==<br />
<br />
The Lon proteolytic domain has a highly '''conserved structure'''. Like its orthologues, namely the eubacterium ''[https://fr.wikipedia.org/wiki/Escherichia_coli E. coli]'' ([https://proteopedia.org/wiki/index.php/1rre 1rre]), and the two archaea ''[https://en.wikipedia.org/wiki/Methanocaldococcus_jannaschii M. jannaschii]'' and ''[https://fr.wikipedia.org/wiki/Archaeoglobus_fulgidus A. fulgidus]'', it presents at its C-terminal a '''Ser-Lys dyad''' responsible of the substrate degradation activity. Although ''h''LonP active site resembles mostly to the one of ''Ec''LonP, the b5-sheet is replaced by an '''extension to a2'''. Thus, the N-terminal region of this helix carries the catalytic serine is a [https://en.wikipedia.org/wiki/310_helix 3(10) helix] and not a b-strand. As a consequence, ''h''LonP has the ability to bring the Asp852 into the active site to '''close''' it by forming a hydrogen bond with Lys898, a property already observed in ''Mj''Lon active site. This inactive state likely makes the catalytic serine inaccessible to the substrate and constraints the pKa of the lysine. Other main structural differences are '''loop shifts''' connecting the secondary structure elements b1 and b2, and a1 <ref>PMID: 20222013</ref>.<br />
<br />
<br />
== Disease ==<br />
<br />
<p align="justify">Various [https://en.wikipedia.org/wiki/Myopathy myopathy], [https://en.wikipedia.org/wiki/Type_2_diabetes type 2 diabetes], [https://en.wikipedia.org/wiki/Parkinson%27s_disease Parkinson's disease], or [https://en.wikipedia.org/wiki/Alzheimer%27s_disease Alzheimer's disease] are human [https://en.wikipedia.org/wiki/Degenerative_disease degenerative disease] partly due to abnormalities of the mitochondria<ref>Wang, N, S Gottesman, M C Willingham, M M Gottesman, and M R Maurizi. “A Human Mitochondrial ATP-Dependent Protease That Is Highly Homologous to Bacterial Lon Protease.” Proceedings of the National Academy of Sciences 90, no. 23 (December 1, 1993): 11247–51. https://doi.org/10.1073/pnas.90.23.11247.<br />
</ref>. In fact, Lon protease has a role in [https://en.wikipedia.org/wiki/Cancer cancer], [https://en.wikipedia.org/wiki/Apoptosis apoptosis] and [https://en.wikipedia.org/wiki/Ageing aging] because this protein is an essential part of developmental pathways and stress response.<br />
<br><br />
[https://en.wikipedia.org/wiki/Mutant Mutant] in Lon decreases the degradation capacity of proteins with abnormal conformations which lead to mitochondrial dysfunction. Mitochondrial dysfunction causes normal cells to become apoptotic, or to aberrant adaptation and selection of hypoxic phenotypes in pathological conditions like cancer<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. <br />
<br><br />
Lon expression is necessary for survival in mammals. Indeed, a [https://en.wikipedia.org/wiki/Zygosity#Homozygous homozygous] [https://en.wikipedia.org/wiki/Deletion_(genetics) deletion] of LONP1 is lethal for early embryonic<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mhttps://proteopedia.org/wiki/skins/common/images/button_extlink.pngitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. Indeed, the [https://rarediseases.info.nih.gov/diseases/1418/codas-syndrome#:~:text=Summary,-Listen&text=Codas%20syndrome%20is%20a%20multiple,Dental%2C%20Auricular%20and%20Skeletal%20anomalies.&text=To%20date%2C%20three%20affected%20children,from%20Brazil)%20have%20been%20reported. CODAS Syndrome] is a rare and multi-system developmental disorder from heterozygous or homozygous mutations in LONP1 where all the affected children were very severely impacted by their disease.<br />
<br><br />
The LONP1 gene is regulated, when the cell undergoes a heat shock, [https://en.wikipedia.org/wiki/Starvation starvation] or oxidative stress the gene is up-regulated. On the contrary, Lon is down-regulated with aging, extensive [https://en.wikipedia.org/wiki/Hypoxia hypoxia], and prolonged oxidative stress. So Lon is an important factor in aging and degenerative disease. <br />
<br><br />
A [https://en.wikipedia.org/wiki/Consensus_sequence consensus] binding site of Nuclear Respiratory Factor 2 (NRF-2) is present on the region -623/+1 of the LONP1 promoter which is important for response to [https://en.wikipedia.org/wiki/Reactive_oxygen_species reactive oxygen species] related to oxidative stress. As well as the putative binding site in -2023/-1230 for [https://en.wikipedia.org/wiki/NF-%CE%BABhttps://en.wikipedia.org/wiki/NF-%CE%BAB NF-kB] in LONP1 which consolidate the role of Lon as a stress protein<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Lon Protease Preferentially Degrades Oxidized Mitochondrial Aconitase by an ATP-Stimulated Mechanism.” Nature Cell Biology 4, no. 9 (September 2002): 674–80. https://doi.org/10.1038/ncb836.</ref>. <br />
<br><br />
Research is being done to use Lon as a therapeutic target for the treatment of cancer by developing novel Lon inhibitors.</p><br />
<br />
<br />
</StructureSection><br />
<br />
== References ==<br />
<references/></div>Rose Buhlmannhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1644&diff=3342129Sandbox Reserved 16442021-01-14T14:35:30Z<p>Rose Buhlmann: </p>
<hr />
<div>{{Sandbox_Reserved_ESBS20_}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==2x36 - Structure of the proteolytic domain of the <scene name='86/868177/Structure_hmlon_protease/1'>Human Mitochondrial Lon protease</scene>==<br />
<StructureSection load='2x36' size='340' side='right' caption='Structure of the Human Mitochondrial Lon protease' scene=''><br />
<br />
<p align="justify">'''2x36''' is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. This domain belongs to the [https://en.wikipedia.org/wiki/Lon_protease_family Lon protease family]. <br />
<br><br />
[https://en.wikipedia.org/wiki/Mitochondrion Mitochondrial] Lon [https://en.wikipedia.org/wiki/Protease protease] is an '''ATP-dependent serine protease''' involved '''in the selective degradation of abnormal proteins'''. [https://en.wikipedia.org/wiki/LONP1 LONP1] situated on chromosome 19 is the nuclear gene encoding mitochondrial Lon protein. The single species of [https://en.wikipedia.org/wiki/Messenger_RNA mRNA] of this protein is found in the mitochondrial matrix. This protein from human tissues has a molecular mass of 100 [https://en.wikipedia.org/wiki/Dalton_(unit) kDA].</p><br />
<br><br />
== Function ==<br />
<br />
<p align="justify">The mitochondrial Lon protease is an '''important regulator of mitochondrial [https://en.wikipedia.org/wiki/Metabolism metabolism]''' including the maintenance and repair of mitochondrial [https://en.wikipedia.org/wiki/DNA DNA]. This protein is also essential for '''homeostasis of mitochondria''', and by regulating some regulatory proteins which have '''a short life or damaged proteins'''. <br />
<br><br />
Lon protease has three main roles<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.<br />
</p>. This protein is able to do a '''[https://en.wikipedia.org/wiki/Proteolysis proteolytic] digestion''' of oxidized proteins which allows the renewal of essential mitochondrial enzymes such as [https://en.wikipedia.org/wiki/Aconitase aconitase] or [https://en.wikipedia.org/wiki/TFAM Mitochondrial transcription factor A].<br />
Lon protease is involved in [https://en.wikipedia.org/wiki/Mitochondrial_DNA mtDNA] [https://en.wikipedia.org/wiki/DNA_replication replication] and [https://en.wikipedia.org/w/index.php?title=Mitogenesis&redirect=no mitogenesis] by being a '''mitochondrial [https://en.wikipedia.org/wiki/DNA-binding_protein DNA-bing protein]'''. Human Lon and mtDNA associate at the level of their at least 4 contiguous [https://en.wikipedia.org/wiki/Guanine guanine] sequence and form a [https://en.wikipedia.org/wiki/G-quadruplex G-quadruplex]<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>.<br />
This protein is able to do a '''[https://en.wikipedia.org/wiki/Proteolysis proteolytic] digestion''' of oxidized proteins which allows the renewal of essential mitochondrial enzymes such as [https://en.wikipedia.org/wiki/Aconitase aconitase] or [https://en.wikipedia.org/wiki/TFAM Mitochondrial transcription factor A].<br />
Lon protease is involved in [https://en.wikipedia.org/wiki/Mitochondrial_DNA mtDNA] [https://en.wikipedia.org/wiki/DNA_replication replication] and [https://en.wikipedia.org/w/index.php?title=Mitogenesis&redirect=no mitogenesis] by being a '''mitochondrial [https://en.wikipedia.org/wiki/DNA-binding_protein DNA-bing protein]'''. Human Lon and mtDNA associate at the level of their at least 4 contiguous [https://en.wikipedia.org/wiki/Guanine guanine] sequence and form '''a [https://en.wikipedia.org/wiki/G-quadruplex G-quadruplex]'''<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. This '''G-rich region''' is the control region for mtDNA replication and transcription<ref>Lu, Bin. “Mitochondrial Lon Protease and Cancer.” Advances in Experimental Medicine and Biology 1038 (2017): 173–82. https://doi.org/10.1007/978-981-10-6674-0_12.</ref>. <br />
<br><br />
<br><br />
Mitochondrial Lon protease interacts with '''[https://en.wikipedia.org/wiki/Chaperone_(protein) protein chaperone]''', notably [https://en.wikipedia.org/wiki/Chaperonin HSP60]-[https://en.wikipedia.org/wiki/Hsp70 Hsp70] complex to protect cell from apoptosis under environmental stress<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>.<br />
<br><br />
The mitochondrial Lon protease is essentially found in '''the cytoplasmic of mitochondria''' because [https://en.wikipedia.org/wiki/Amino_acid amino-acid] has a potential mitochondrial targetting presequences<ref>García-Nafría, Javier, Gabriela Ondrovičová, Elena Blagova, Vladimir M Levdikov, Jacob A Bauer, Carolyn K Suzuki, Eva Kutejová, Anthony J Wilkinson, and Keith S Wilson. “Structure of the Catalytic Domain of the Human Mitochondrial Lon Protease: Proposed Relation of Oligomer Formation and Activity.” Protein Science : A Publication of the Protein Society 19, no. 5 (May 2010): 987–99. https://doi.org/10.1002/pro.376.</ref>. To achieve proteolytic cleavage, the Lon protein has to form '''a hexamer'''. <br />
<br><br />
Lon Human protease alternates between cycles of '''being bound to the mitochondrial genome''' and '''being free into the mitochondrial cytoplasm''' where it can degrade abnormal proteins coming from damaged proteins, errors in the synthesis, or [https://en.wikipedia.org/wiki/Protein_folding misfolded] of multimeric proteins. Its inactive conformation prevents '''uncontrolled proteolysis'''. <br />
Lon protease has also a role in '''mtDNA quality control''' by permits oxidative mitochondrial DNA damage. Sensitivities of H2O2-induced mtDNA damage depend on the proportion of LON<ref>Lu, Bin. “Mitochondrial Lon Protease and Cancer.” Advances in Experimental Medicine and Biology 1038 (2017): 173–82. https://doi.org/10.1007/978-981-10-6674-0_12.</ref>. <br />
Other ATP-dependent proteases are found in eukaryotic cells and organelles like [https://en.wikipedia.org/wiki/Proteasome_endopeptidase_complex 26S protease] which uses [https://en.wikipedia.org/wiki/ATP_hydrolysis ATP hydrolysis] for conjugation or ubiquitin for example.</p><br />
<br><br />
<br />
== General structure ==<br />
<br />
<p align="justify">Lon proteins are grouped into two families, '''LonA''' and '''LonB'''. The human protein LonP1 is part of the LonA proteins <ref>« The N-terminal domain plays a crucial role in the structure of a full-length human mitochondrial Lon protease | Scientific Reports ». Consulté le 13 janvier 2021. https://www.nature.com/articles/srep33631.<br />
</ref>. This protein has three isoforms obtained by [https://en.wikipedia.org/wiki/Alternative_splicing alternative splicing] of the portion of DNA coding for this protein <ref>He, Lihong, Dongyang Luo, Fan Yang, Chunhao Li, Xuegong Zhang, Haiteng Deng, et Jing-Ren Zhang. « Multiple domains of bacterial and human Lon proteases define substrate selectivity ». Emerging Microbes & Infections 7 (17 août 2018). https://doi.org/10.1038/s41426-018-0148-4.<br />
</ref>.<br />
Globally there is a great diversity of Lon proteins, but they are all organised in an oligomeric ring structure, mostly hexameric structure with identical subunits.<br />
Lon proteins are therefore an hexameric chambered [https://en.wikipedia.org/wiki/Protease protease] complex. (This structure is similar with yeast [https://www.yeastgenome.org/locus/S000000118 Pim1] )<br />
The six Lon monomers are forming three pairs of legs owned by the N-terminal domain of the protein. This structure is emerging of the protein as a trimer of dimers <ref>Kutejová, Eva. « Mitochondrial Lon protease-unique structure and essential function in mammalian cells ». Integrative Cancer Science and Therapeutics 5, nᵒ 6 (2018). https://doi.org/10.15761/ICST.1000296.<br />
</ref>.<br />
<br><br />
Like many proteins, Lon is a '''flexible''' peptide which has different '''three-dimensional conformations'''. The protein can therefore pass from one conformation to another by hydrolysis of [https://biologydictionary.net/atp/ ATP]<ref>Voos, Wolfgang, et Karen Pollecker. « The Mitochondrial Lon Protease: Novel Functions off the Beaten Track? » Biomolecules 10, nᵒ 2 (7 février 2020). https://doi.org/10.3390/biom10020253.<br />
</ref>.<br />
With these conformational changes, the [https://en.wikipedia.org/wiki/Active_site '''active sites'''] of the Lon protein are protected from the external environment in the oligomeric complex that forms the '''degradation chamber'''.<br />
This form of degradation chamber is also found in bacteria, plants, fungi and metazoan, the similarities with bacteria are most probably due to the [https://en.wikipedia.org/wiki/Symbiogenesis endosymbiotic theory].<br />
<br><br />
<br><br />
This protein has a [https://en.wikipedia.org/wiki/Proteolysis '''proteolytic'''] and [https://en.wikipedia.org/wiki/Chaperone_(protein) '''chaperone''']-like activity, it cannot unfold aggregated proteins, but can participate in the assembling of some complexes). These two enzymatic activities are separated on two polypeptide chains forming a complex or two separate domains on the same polypeptide chain.<br />
<br><br />
The Lon protein has three main distinct domains: the first, the '''N-terminal''' domain, is specialised in '''substrate binding''' and [https://en.wikipedia.org/wiki/Oligomer '''oligomerization''']. The second, called the '''AAA+ domain''' (or A domain) corresponds to the fixation and hydrolysis site of the [https://biologydictionary.net/atp/ATP ATP]. Finally, the third domain located at the '''C-terminal''' is an active serine site leading to '''substrate degradation'''. This is a [https://en.wikipedia.org/wiki/Proteolysis '''proteolytic'''] domain, called domain P <ref>He, Lihong, Dongyang Luo, Fan Yang, Chunhao Li, Xuegong Zhang, Haiteng Deng, et Jing-Ren Zhang. « Multiple domains of bacterial and human Lon proteases define substrate selectivity ». Emerging Microbes & Infections 7 (17 août 2018). https://doi.org/10.1038/s41426-018-0148-4.<br />
</ref>.<br />
<br><br />
Mammalian Lon protein only interacts with '''single-stranded DNA''' (ssDNA) but not dsDNA. There are therefore special sequences for interaction with '''G-rich DNA''' as well as RNA. In addition, the binding of a substrate to the protein stimulates the interaction with the DNA.<br />
[https://en.wikipedia.org/wiki/Mitochondrial_DNA mtDNA] binds to the Lon protein with different affinities depending on the state of the cell and the type of cell meeting the following four parameters <ref>Lu, Bin, Swati Yadav, Parul G. Shah, Tong Liu, Bin Tian, Sebastian Pukszta, Nerissa Villaluna, et al. « Roles for the Human ATP-Dependent Lon Protease in Mitochondrial DNA Maintenance ». Journal of Biological Chemistry 282, nᵒ 24 (15 juin 2007): 17363‑74. https://doi.org/10.1074/jbc.M611540200.<br />
</ref>: <br />
<br><br />
- the single stranding state of mtDNA<br />
<br><br />
- the bioavailability of the mtDNA binding sites<br />
<br><br />
- the affinity of the protein for a given DNA sequence<br />
<br><br />
- the total number of high and low affinity Lon binding sites present</p><br />
<br />
<br />
<br />
<br />
== Structural highlights ==<br />
<br />
== Evolutionary conservation ==<br />
<br />
The Lon proteolytic domain has a highly '''conserved structure'''. Like its orthologues, namely the eubacterium ''[https://fr.wikipedia.org/wiki/Escherichia_coli E. coli]'' ([https://proteopedia.org/wiki/index.php/1rre 1rre]), and the two archaea ''[https://en.wikipedia.org/wiki/Methanocaldococcus_jannaschii M. jannaschii]'' and ''[https://fr.wikipedia.org/wiki/Archaeoglobus_fulgidus A. fulgidus]'', it presents at its C-terminal a '''Ser-Lys dyad''' responsible of the substrate degradation activity. Although ''h''LonP active site resembles mostly to the one of ''Ec''LonP, the b5-sheet is replaced by an '''extension to a2'''. Thus, the N-terminal region of this helix carries the catalytic serine is a [https://en.wikipedia.org/wiki/310_helix 3(10) helix] and not a b-strand. As a consequence, ''h''LonP has the ability to bring the Asp852 into the active site to '''close''' it by forming a hydrogen bond with Lys898, a property already observed in ''Mj''Lon active site. This inactive state likely makes the catalytic serine inaccessible to the substrate and constraints the pKa of the lysine. Other main structural differences are '''loop shifts''' connecting the secondary structure elements b1 and b2, and a1<ref>PMID: 20222013</ref>.<br />
<br />
<br />
== Disease ==<br />
<br />
<p align="justify">Various [https://en.wikipedia.org/wiki/Myopathy myopathy], [https://en.wikipedia.org/wiki/Type_2_diabetes type 2 diabetes], [https://en.wikipedia.org/wiki/Parkinson%27s_disease Parkinson's disease], or [https://en.wikipedia.org/wiki/Alzheimer%27s_disease Alzheimer's disease] are human [https://en.wikipedia.org/wiki/Degenerative_disease degenerative disease] partly due to abnormalities of the mitochondria<ref>Wang, N, S Gottesman, M C Willingham, M M Gottesman, and M R Maurizi. “A Human Mitochondrial ATP-Dependent Protease That Is Highly Homologous to Bacterial Lon Protease.” Proceedings of the National Academy of Sciences 90, no. 23 (December 1, 1993): 11247–51. https://doi.org/10.1073/pnas.90.23.11247.<br />
</ref>. In fact, Lon protease has a role in [https://en.wikipedia.org/wiki/Cancer cancer], [https://en.wikipedia.org/wiki/Apoptosis apoptosis] and [https://en.wikipedia.org/wiki/Ageing aging] because this protein is an essential part of developmental pathways and stress response.<br />
<br><br />
[https://en.wikipedia.org/wiki/Mutant Mutant] in Lon decreases the degradation capacity of proteins with abnormal conformations which lead to mitochondrial dysfunction. Mitochondrial dysfunction causes normal cells to become apoptotic, or to aberrant adaptation and selection of hypoxic phenotypes in pathological conditions like cancer<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. <br />
<br><br />
Lon expression is necessary for survival in mammals. Indeed, a [https://en.wikipedia.org/wiki/Zygosity#Homozygous homozygous] [https://en.wikipedia.org/wiki/Deletion_(genetics) deletion] of LONP1 is lethal for early embryonic<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mhttps://proteopedia.org/wiki/skins/common/images/button_extlink.pngitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. Indeed, the [https://rarediseases.info.nih.gov/diseases/1418/codas-syndrome#:~:text=Summary,-Listen&text=Codas%20syndrome%20is%20a%20multiple,Dental%2C%20Auricular%20and%20Skeletal%20anomalies.&text=To%20date%2C%20three%20affected%20children,from%20Brazil)%20have%20been%20reported. CODAS Syndrome] is a rare and multi-system developmental disorder from heterozygous or homozygous mutations in LONP1 where all the affected children were very severely impacted by their disease.<br />
<br><br />
The LONP1 gene is regulated, when the cell undergoes a heat shock, [https://en.wikipedia.org/wiki/Starvation starvation] or oxidative stress the gene is up-regulated. On the contrary, Lon is down-regulated with aging, extensive [https://en.wikipedia.org/wiki/Hypoxia hypoxia], and prolonged oxidative stress. So Lon is an important factor in aging and degenerative disease. <br />
<br><br />
A [https://en.wikipedia.org/wiki/Consensus_sequence consensus] binding site of Nuclear Respiratory Factor 2 (NRF-2) is present on the region -623/+1 of the LONP1 promoter which is important for response to [https://en.wikipedia.org/wiki/Reactive_oxygen_species reactive oxygen species] related to oxidative stress. As well as the putative binding site in -2023/-1230 for [https://en.wikipedia.org/wiki/NF-%CE%BABhttps://en.wikipedia.org/wiki/NF-%CE%BAB NF-kB] in LONP1 which consolidate the role of Lon as a stress protein<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Lon Protease Preferentially Degrades Oxidized Mitochondrial Aconitase by an ATP-Stimulated Mechanism.” Nature Cell Biology 4, no. 9 (September 2002): 674–80. https://doi.org/10.1038/ncb836.</ref>. <br />
<br><br />
Research is being done to use Lon as a therapeutic target for the treatment of cancer by developing novel Lon inhibitors.</p><br />
<br />
<br />
</StructureSection><br />
<br />
== References ==<br />
<references/></div>Rose Buhlmannhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1644&diff=3342119Sandbox Reserved 16442021-01-14T14:14:26Z<p>Rose Buhlmann: </p>
<hr />
<div>{{Sandbox_Reserved_ESBS20_}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==2x36 - Structure of the proteolytic domain of the <scene name='86/868177/Structure_hmlon_protease/1'>Human Mitochondrial Lon protease</scene>==<br />
<StructureSection load='2x36' size='340' side='right' caption='Structure of the Human Mitochondrial Lon protease' scene=''><br />
<br />
<p align="justify">'''2x36''' is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. This domain belongs to the [https://en.wikipedia.org/wiki/Lon_protease_family Lon protease family]. <br />
<br><br />
[https://en.wikipedia.org/wiki/Mitochondrion Mitochondrial] Lon [https://en.wikipedia.org/wiki/Protease protease] is an '''ATP-dependent serine protease''' involved '''in the selective degradation of abnormal proteins'''. [https://en.wikipedia.org/wiki/LONP1 LONP1] situated on chromosome 19 is the nuclear gene encoding mitochondrial Lon protein. The single species of [https://en.wikipedia.org/wiki/Messenger_RNA mRNA] of this protein is found in the mitochondrial matrix. This protein from human tissues has a molecular mass of 100 [https://en.wikipedia.org/wiki/Dalton_(unit) kDA].</p><br />
<br><br />
== Function ==<br />
<br />
<p align="justify">The mitochondrial Lon protease is an '''important regulator of mitochondrial [https://en.wikipedia.org/wiki/Metabolism metabolism]''' including the maintenance and repair of mitochondrial [https://en.wikipedia.org/wiki/DNA DNA]. This protein is also essential for '''homeostasis of mitochondria''', and by regulating some regulatory proteins which have '''a short life or damaged proteins'''. <br />
<br><br />
Lon protease has three main roles. <br />
This protein is able to do a '''[https://en.wikipedia.org/wiki/Proteolysis proteolytic] digestion''' of oxidized proteins which allows the renewal of essential mitochondrial enzymes such as [https://en.wikipedia.org/wiki/Aconitase aconitase] or [https://en.wikipedia.org/wiki/TFAM Mitochondrial transcription factor A].<br />
Lon protease is involved in [https://en.wikipedia.org/wiki/Mitochondrial_DNA mtDNA] [https://en.wikipedia.org/wiki/DNA_replication replication] and [https://en.wikipedia.org/w/index.php?title=Mitogenesis&redirect=no mitogenesis] by being a '''mitochondrial [https://en.wikipedia.org/wiki/DNA-binding_protein DNA-bing protein]'''. Human Lon and mtDNA associate at the level of their at least 4 contiguous [https://en.wikipedia.org/wiki/Guanine guanine] sequence and form '''a [https://en.wikipedia.org/wiki/G-quadruplex G-quadruplex]'''<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. This '''G-rich region''' is the control region for mtDNA replication and transcription<ref>Lu, Bin. “Mitochondrial Lon Protease and Cancer.” Advances in Experimental Medicine and Biology 1038 (2017): 173–82. https://doi.org/10.1007/978-981-10-6674-0_12.</ref>. <br />
<br><br />
<br><br />
Mitochondrial Lon protease interacts with '''[https://en.wikipedia.org/wiki/Chaperone_(protein) protein chaperone]''', notably [https://en.wikipedia.org/wiki/Chaperonin HSP60]-[https://en.wikipedia.org/wiki/Hsp70 Hsp70] complex to protect cell from apoptosis under environmental stress<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>.<br />
<br><br />
The mitochondrial Lon protease is essentially found in '''the cytoplasmic of mitochondria''' because [https://en.wikipedia.org/wiki/Amino_acid amino-acid] has a potential mitochondrial targetting presequences<ref>García-Nafría, Javier, Gabriela Ondrovičová, Elena Blagova, Vladimir M Levdikov, Jacob A Bauer, Carolyn K Suzuki, Eva Kutejová, Anthony J Wilkinson, and Keith S Wilson. “Structure of the Catalytic Domain of the Human Mitochondrial Lon Protease: Proposed Relation of Oligomer Formation and Activity.” Protein Science : A Publication of the Protein Society 19, no. 5 (May 2010): 987–99. https://doi.org/10.1002/pro.376.</ref>. To achieve proteolytic cleavage, the Lon protein has to form '''a hexamer'''. <br />
<br><br />
Lon Human protease alternates between cycles of '''being bound to the mitochondrial genome''' and '''being free into the mitochondrial cytoplasm''' where it can degrade abnormal proteins coming from damaged proteins, errors in the synthesis, or [https://en.wikipedia.org/wiki/Protein_folding misfolded] of multimeric proteins. Its inactive conformation prevents '''uncontrolled proteolysis'''. <br />
Lon protease has also a role in '''mtDNA quality control''' by permits oxidative mitochondrial DNA damage. Sensitivities of H2O2-induced mtDNA damage depend on the proportion of LON<ref>Lu, Bin. “Mitochondrial Lon Protease and Cancer.” Advances in Experimental Medicine and Biology 1038 (2017): 173–82. https://doi.org/10.1007/978-981-10-6674-0_12.</ref>. <br />
Other ATP-dependent proteases are found in eukaryotic cells and organelles like [https://en.wikipedia.org/wiki/Proteasome_endopeptidase_complex 26S protease] which uses [https://en.wikipedia.org/wiki/ATP_hydrolysis ATP hydrolysis] for conjugation or ubiquitin for example.</p><br />
<br><br />
<br />
== General structure ==<br />
<br />
<p align="justify">Lon proteins are grouped into two families, '''LonA''' and '''LonB'''. The human protein LonP1 is part of the LonA proteins <ref>« The N-terminal domain plays a crucial role in the structure of a full-length human mitochondrial Lon protease | Scientific Reports ». Consulté le 13 janvier 2021. https://www.nature.com/articles/srep33631.<br />
</ref>. This protein has three isoforms obtained by [https://en.wikipedia.org/wiki/Alternative_splicing alternative splicing] of the portion of DNA coding for this protein <ref>He, Lihong, Dongyang Luo, Fan Yang, Chunhao Li, Xuegong Zhang, Haiteng Deng, et Jing-Ren Zhang. « Multiple domains of bacterial and human Lon proteases define substrate selectivity ». Emerging Microbes & Infections 7 (17 août 2018). https://doi.org/10.1038/s41426-018-0148-4.<br />
</ref>.<br />
Globally there is a great diversity of Lon proteins, but they are all organised in an oligomeric ring structure, mostly hexameric structure with identical subunits.<br />
Lon proteins are therefore an hexameric chambered [https://en.wikipedia.org/wiki/Protease protease] complex. (This structure is similar with yeast [https://www.yeastgenome.org/locus/S000000118 Pim1] )<br />
The six Lon monomers are forming three pairs of legs owned by the N-terminal domain of the protein. This structure is emerging of the protein as a trimer of dimers <ref>Kutejová, Eva. « Mitochondrial Lon protease-unique structure and essential function in mammalian cells ». Integrative Cancer Science and Therapeutics 5, nᵒ 6 (2018). https://doi.org/10.15761/ICST.1000296.<br />
</ref>.<br />
<br><br />
Like many proteins, Lon is a '''flexible''' peptide which has different '''three-dimensional conformations'''. The protein can therefore pass from one conformation to another by hydrolysis of [https://biologydictionary.net/atp/ ATP]<ref>Voos, Wolfgang, et Karen Pollecker. « The Mitochondrial Lon Protease: Novel Functions off the Beaten Track? » Biomolecules 10, nᵒ 2 (7 février 2020). https://doi.org/10.3390/biom10020253.<br />
</ref>.<br />
With these conformational changes, the [https://en.wikipedia.org/wiki/Active_site '''active sites'''] of the Lon protein are protected from the external environment in the oligomeric complex that forms the '''degradation chamber'''.<br />
This form of degradation chamber is also found in bacteria, plants, fungi and metazoan, the similarities with bacteria are most probably due to the [https://en.wikipedia.org/wiki/Symbiogenesis endosymbiotic theory].<br />
<br><br />
<br><br />
This protein has a [https://en.wikipedia.org/wiki/Proteolysis '''proteolytic'''] and [https://en.wikipedia.org/wiki/Chaperone_(protein) '''chaperone''']-like activity, it cannot unfold aggregated proteins, but can participate in the assembling of some complexes). These two enzymatic activities are separated on two polypeptide chains forming a complex or two separate domains on the same polypeptide chain.<br />
<br><br />
The Lon protein has three main distinct domains: the first, the '''N-terminal''' domain, is specialised in '''substrate binding''' and [https://en.wikipedia.org/wiki/Oligomer '''oligomerization''']. The second, called the '''AAA+ domain''' (or A domain) corresponds to the fixation and hydrolysis site of the [https://biologydictionary.net/atp/ATP ATP]. Finally, the third domain located at the '''C-terminal''' is an active serine site leading to '''substrate degradation'''. This is a [https://en.wikipedia.org/wiki/Proteolysis '''proteolytic'''] domain, called domain P <ref>He, Lihong, Dongyang Luo, Fan Yang, Chunhao Li, Xuegong Zhang, Haiteng Deng, et Jing-Ren Zhang. « Multiple domains of bacterial and human Lon proteases define substrate selectivity ». Emerging Microbes & Infections 7 (17 août 2018). https://doi.org/10.1038/s41426-018-0148-4.<br />
</ref>.<br />
<br><br />
Mammalian Lon protein only interacts with '''single-stranded DNA''' (ssDNA) but not dsDNA. There are therefore special sequences for interaction with '''G-rich DNA''' as well as RNA. In addition, the binding of a substrate to the protein stimulates the interaction with the DNA.<br />
[https://en.wikipedia.org/wiki/Mitochondrial_DNA mtDNA] binds to the Lon protein with different affinities depending on the state of the cell and the type of cell meeting the following four parameters <ref>Lu, Bin, Swati Yadav, Parul G. Shah, Tong Liu, Bin Tian, Sebastian Pukszta, Nerissa Villaluna, et al. « Roles for the Human ATP-Dependent Lon Protease in Mitochondrial DNA Maintenance ». Journal of Biological Chemistry 282, nᵒ 24 (15 juin 2007): 17363‑74. https://doi.org/10.1074/jbc.M611540200.<br />
</ref>: <br />
<br><br />
- the single stranding state of mtDNA<br />
<br><br />
- the bioavailability of the mtDNA binding sites<br />
<br><br />
- the affinity of the protein for a given DNA sequence<br />
<br><br />
- the total number of high and low affinity Lon binding sites present</p><br />
<br />
<br />
<br />
<br />
== Structural highlights ==<br />
<br />
== Evolutionary conservation ==<br />
<br />
The Lon proteolytic domain has a highly '''conserved structure'''. Like its orthologues, namely the eubacterium ''[https://fr.wikipedia.org/wiki/Escherichia_coli E. coli]'' ([https://proteopedia.org/wiki/index.php/1rre 1rre]), and the two archaea ''[https://en.wikipedia.org/wiki/Methanocaldococcus_jannaschii M. jannaschii]'' and ''[https://fr.wikipedia.org/wiki/Archaeoglobus_fulgidus A. fulgidus]'', it presents at its C-terminal a '''Ser-Lys dyad''' responsible of the substrate degradation activity. Although ''h''LonP active site resembles mostly to the one of ''Ec''LonP, the b5-sheet is replaced by an '''extension to a2'''. Thus, the N-terminal region of this helix carries the catalytic serine is a [https://en.wikipedia.org/wiki/310_helix 3(10) helix] and not a b-strand. As a consequence, ''h''LonP has the ability to bring the Asp852 into the active site to '''close''' it by forming a hydrogen bond with Lys898, a property already observed in ''Mj''Lon active site. This inactive state likely makes the catalytic serine inaccessible to the substrate and constraints the pKa of the lysine. Other main structural differences are '''loop shifts''' connecting the secondary structure elements b1 and b2, and a1.<br />
<br />
== Disease ==<br />
<br />
<p align="justify">Various [https://en.wikipedia.org/wiki/Myopathy myopathy], [https://en.wikipedia.org/wiki/Type_2_diabetes type 2 diabetes], [https://en.wikipedia.org/wiki/Parkinson%27s_disease Parkinson's disease], or [https://en.wikipedia.org/wiki/Alzheimer%27s_disease Alzheimer's disease] are human [https://en.wikipedia.org/wiki/Degenerative_disease degenerative disease] partly due to abnormalities of the mitochondria<ref>Wang, N, S Gottesman, M C Willingham, M M Gottesman, and M R Maurizi. “A Human Mitochondrial ATP-Dependent Protease That Is Highly Homologous to Bacterial Lon Protease.” Proceedings of the National Academy of Sciences 90, no. 23 (December 1, 1993): 11247–51. https://doi.org/10.1073/pnas.90.23.11247.<br />
</ref>. In fact, Lon protease has a role in [https://en.wikipedia.org/wiki/Cancer cancer], [https://en.wikipedia.org/wiki/Apoptosis apoptosis] and [https://en.wikipedia.org/wiki/Ageing aging] because this protein is an essential part of developmental pathways and stress response.<br />
<br><br />
[https://en.wikipedia.org/wiki/Mutant Mutant] in Lon decreases the degradation capacity of proteins with abnormal conformations which lead to mitochondrial dysfunction. Mitochondrial dysfunction causes normal cells to become apoptotic, or to aberrant adaptation and selection of hypoxic phenotypes in pathological conditions like cancer<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. <br />
<br><br />
Lon expression is necessary for survival in mammals. Indeed, a [https://en.wikipedia.org/wiki/Zygosity#Homozygous homozygous] [https://en.wikipedia.org/wiki/Deletion_(genetics) deletion] of LONP1 is lethal for early embryonic<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mhttps://proteopedia.org/wiki/skins/common/images/button_extlink.pngitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. Indeed, the [https://rarediseases.info.nih.gov/diseases/1418/codas-syndrome#:~:text=Summary,-Listen&text=Codas%20syndrome%20is%20a%20multiple,Dental%2C%20Auricular%20and%20Skeletal%20anomalies.&text=To%20date%2C%20three%20affected%20children,from%20Brazil)%20have%20been%20reported. CODAS Syndrome] is a rare and multi-system developmental disorder from heterozygous or homozygous mutations in LONP1 where all the affected children were very severely impacted by their disease.<br />
<br><br />
The LONP1 gene is regulated, when the cell undergoes a heat shock, [https://en.wikipedia.org/wiki/Starvation starvation] or oxidative stress the gene is up-regulated. On the contrary, Lon is down-regulated with aging, extensive [https://en.wikipedia.org/wiki/Hypoxia hypoxia], and prolonged oxidative stress. So Lon is an important factor in aging and degenerative disease. <br />
<br><br />
A [https://en.wikipedia.org/wiki/Consensus_sequence consensus] binding site of Nuclear Respiratory Factor 2 (NRF-2) is present on the region -623/+1 of the LONP1 promoter which is important for response to [https://en.wikipedia.org/wiki/Reactive_oxygen_species reactive oxygen species] related to oxidative stress. As well as the putative binding site in -2023/-1230 for [https://en.wikipedia.org/wiki/NF-%CE%BABhttps://en.wikipedia.org/wiki/NF-%CE%BAB NF-kB] in LONP1 which consolidate the role of Lon as a stress protein<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Lon Protease Preferentially Degrades Oxidized Mitochondrial Aconitase by an ATP-Stimulated Mechanism.” Nature Cell Biology 4, no. 9 (September 2002): 674–80. https://doi.org/10.1038/ncb836.</ref>. <br />
<br><br />
Research is being done to use Lon as a therapeutic target for the treatment of cancer by developing novel Lon inhibitors.</p><br />
<br />
<br />
<br><br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Rose Buhlmannhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1644&diff=3342113Sandbox Reserved 16442021-01-14T14:03:44Z<p>Rose Buhlmann: </p>
<hr />
<div>{{Sandbox_Reserved_ESBS20_}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==2x36 - Structure of the proteolytic domain of the <scene name='86/868177/Structure_hmlon_protease/1'>Human Mitochondrial Lon protease</scene>==<br />
<StructureSection load='2x36' size='340' side='right' caption='Structure of the Human Mitochondrial Lon protease' scene=''><br />
<br />
<p align="justify">'''2x36''' is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. This domain belongs to the [https://en.wikipedia.org/wiki/Lon_protease_family Lon protease family]. <br />
<br><br />
[https://en.wikipedia.org/wiki/Mitochondrion Mitochondrial] Lon [https://en.wikipedia.org/wiki/Protease protease] is an '''ATP-dependent serine protease''' involved '''in the selective degradation of abnormal proteins'''. [https://en.wikipedia.org/wiki/LONP1 LONP1] situated on chromosome 19 is the nuclear gene encoding mitochondrial Lon protein. The single species of [https://en.wikipedia.org/wiki/Messenger_RNA mRNA] of this protein is found in the mitochondrial matrix. This protein from human tissues has a molecular mass of 100 [https://en.wikipedia.org/wiki/Dalton_(unit) kDA].</p><br />
<br><br />
== Function ==<br />
<br />
<p align="justify">The mitochondrial Lon protease is an '''important regulator of mitochondrial [https://en.wikipedia.org/wiki/Metabolism metabolism]''' including the maintenance and repair of mitochondrial [https://en.wikipedia.org/wiki/DNA DNA]. This protein is also essential for '''homeostasis of mitochondria''', and by regulating some regulatory proteins which have '''a short life or damaged proteins'''. <br />
<br><br />
Lon protease has three main roles. <br />
This protein is able to do a '''[https://en.wikipedia.org/wiki/Proteolysis proteolytic] digestion''' of oxidized proteins which allows the renewal of essential mitochondrial enzymes such as [https://en.wikipedia.org/wiki/Aconitase aconitase] or [https://en.wikipedia.org/wiki/TFAM Mitochondrial transcription factor A].<br />
Lon protease is involved in [https://en.wikipedia.org/wiki/Mitochondrial_DNA mtDNA] [https://en.wikipedia.org/wiki/DNA_replication replication] and [https://en.wikipedia.org/w/index.php?title=Mitogenesis&redirect=no mitogenesis] by being a '''mitochondrial [https://en.wikipedia.org/wiki/DNA-binding_protein DNA-bing protein]'''. Human Lon and mtDNA associate at the level of their at least 4 contiguous [https://en.wikipedia.org/wiki/Guanine guanine] sequence and form '''a [https://en.wikipedia.org/wiki/G-quadruplex G-quadruplex]'''<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. This '''G-rich region''' is the control region for mtDNA replication and transcription<ref>Lu, Bin. “Mitochondrial Lon Protease and Cancer.” Advances in Experimental Medicine and Biology 1038 (2017): 173–82. https://doi.org/10.1007/978-981-10-6674-0_12.</ref>. <br />
<br><br />
Mitochondrial Lon protease interacts with '''[https://en.wikipedia.org/wiki/Chaperone_(protein) protein chaperone]''', notably [https://en.wikipedia.org/wiki/Chaperonin HSP60]-[https://en.wikipedia.org/wiki/Hsp70 Hsp70] complex to protect cell from apoptosis under environmental stress<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>.<br />
<br><br />
The mitochondrial Lon protease is essentially found in '''the cytoplasmic of mitochondria''' because [https://en.wikipedia.org/wiki/Amino_acid amino-acid] has a potential mitochondrial targetting presequences<ref>García-Nafría, Javier, Gabriela Ondrovičová, Elena Blagova, Vladimir M Levdikov, Jacob A Bauer, Carolyn K Suzuki, Eva Kutejová, Anthony J Wilkinson, and Keith S Wilson. “Structure of the Catalytic Domain of the Human Mitochondrial Lon Protease: Proposed Relation of Oligomer Formation and Activity.” Protein Science : A Publication of the Protein Society 19, no. 5 (May 2010): 987–99. https://doi.org/10.1002/pro.376.</ref>.<br />
<br><br />
Lon Human protease alternates between cycles of '''being bound to the mitochondrial genome''' and '''being free into the mitochondrial cytoplasm''' where it can degrade abnormal proteins coming from damaged proteins, errors in the synthesis, or [https://en.wikipedia.org/wiki/Protein_folding misfolded] of multimeric proteins. Its inactive conformation prevents '''uncontrolled proteolysis'''. <br />
To achieve proteolytic cleavage, the Lon protein has to form '''a hexamer'''. <br />
Lon protease has also a role in '''mtDNA quality control''' by permits oxidative mitochondrial DNA damage. Sensitivities of H2O2-induced mtDNA damage depend on the proportion of LON<ref>Lu, Bin. “Mitochondrial Lon Protease and Cancer.” Advances in Experimental Medicine and Biology 1038 (2017): 173–82. https://doi.org/10.1007/978-981-10-6674-0_12.</ref>. <br />
Other ATP-dependent proteases are found in eukaryotic cells and organelles like [https://en.wikipedia.org/wiki/Proteasome_endopeptidase_complex 26S protease] which uses [https://en.wikipedia.org/wiki/ATP_hydrolysis ATP hydrolysis] for conjugation or ubiquitin for example.</p><br />
<br><br />
<br />
== General structure ==<br />
<br />
<p align="justify">Lon proteins are grouped into two families, '''LonA''' and '''LonB'''. The human protein LonP1 is part of the LonA proteins <ref>« The N-terminal domain plays a crucial role in the structure of a full-length human mitochondrial Lon protease | Scientific Reports ». Consulté le 13 janvier 2021. https://www.nature.com/articles/srep33631.<br />
</ref>. This protein has three isoforms obtained by [https://en.wikipedia.org/wiki/Alternative_splicing alternative splicing] of the portion of DNA coding for this protein <ref>He, Lihong, Dongyang Luo, Fan Yang, Chunhao Li, Xuegong Zhang, Haiteng Deng, et Jing-Ren Zhang. « Multiple domains of bacterial and human Lon proteases define substrate selectivity ». Emerging Microbes & Infections 7 (17 août 2018). https://doi.org/10.1038/s41426-018-0148-4.<br />
</ref>.<br />
Globally there is a great diversity of Lon proteins, but they are all organised in an oligomeric ring structure, mostly hexameric structure with identical subunits.<br />
Lon proteins are therefore an hexameric chambered [https://en.wikipedia.org/wiki/Protease protease] complex. (This structure is similar with yeast [https://www.yeastgenome.org/locus/S000000118 Pim1] )<br />
The six Lon monomers are forming three pairs of legs owned by the N-terminal domain of the protein. This structure is emerging of the protein as a trimer of dimers <ref>Kutejová, Eva. « Mitochondrial Lon protease-unique structure and essential function in mammalian cells ». Integrative Cancer Science and Therapeutics 5, nᵒ 6 (2018). https://doi.org/10.15761/ICST.1000296.<br />
</ref>.<br />
<br><br />
Like many proteins, Lon is a '''flexible''' peptide which has different '''three-dimensional conformations'''. The protein can therefore pass from one conformation to another by hydrolysis of [https://biologydictionary.net/atp/ ATP]<ref>Voos, Wolfgang, et Karen Pollecker. « The Mitochondrial Lon Protease: Novel Functions off the Beaten Track? » Biomolecules 10, nᵒ 2 (7 février 2020). https://doi.org/10.3390/biom10020253.<br />
</ref>.<br />
With these conformational changes, the [https://en.wikipedia.org/wiki/Active_site '''active sites'''] of the Lon protein are protected from the external environment in the oligomeric complex that forms the '''degradation chamber'''.<br />
This form of degradation chamber is also found in bacteria, plants, fungi and metazoan, the similarities with bacteria are most probably due to the [https://en.wikipedia.org/wiki/Symbiogenesis endosymbiotic theory].<br />
<br><br />
<br><br />
This protein has a [https://en.wikipedia.org/wiki/Proteolysis '''proteolytic'''] and [https://en.wikipedia.org/wiki/Chaperone_(protein) '''chaperone''']-like activity, it cannot unfold aggregated proteins, but can participate in the assembling of some complexes). These two enzymatic activities are separated on two polypeptide chains forming a complex or two separate domains on the same polypeptide chain.<br />
<br><br />
The Lon protein has three main distinct domains: the first, the '''N-terminal''' domain, is specialised in '''substrate binding''' and [https://en.wikipedia.org/wiki/Oligomer '''oligomerization''']. The second, called the '''AAA+ domain''' (or A domain) corresponds to the fixation and hydrolysis site of the [https://biologydictionary.net/atp/ATP ATP]. Finally, the third domain located at the '''C-terminal''' is an active serine site leading to '''substrate degradation'''. This is a [https://en.wikipedia.org/wiki/Proteolysis '''proteolytic'''] domain, called domain P <ref>He, Lihong, Dongyang Luo, Fan Yang, Chunhao Li, Xuegong Zhang, Haiteng Deng, et Jing-Ren Zhang. « Multiple domains of bacterial and human Lon proteases define substrate selectivity ». Emerging Microbes & Infections 7 (17 août 2018). https://doi.org/10.1038/s41426-018-0148-4.<br />
</ref>.<br />
<br><br />
Mammalian Lon protein only interacts with '''single-stranded DNA''' (ssDNA) but not dsDNA. There are therefore special sequences for interaction with '''G-rich DNA''' as well as RNA. In addition, the binding of a substrate to the protein stimulates the interaction with the DNA.<br />
[https://en.wikipedia.org/wiki/Mitochondrial_DNA mtDNA] binds to the Lon protein with different affinities depending on the state of the cell and the type of cell meeting the following four parameters <ref>Lu, Bin, Swati Yadav, Parul G. Shah, Tong Liu, Bin Tian, Sebastian Pukszta, Nerissa Villaluna, et al. « Roles for the Human ATP-Dependent Lon Protease in Mitochondrial DNA Maintenance ». Journal of Biological Chemistry 282, nᵒ 24 (15 juin 2007): 17363‑74. https://doi.org/10.1074/jbc.M611540200.<br />
</ref>: <br />
<br><br />
- the single stranding state of mtDNA<br />
<br><br />
- the bioavailability of the mtDNA binding sites<br />
<br><br />
- the affinity of the protein for a given DNA sequence<br />
<br><br />
- the total number of high and low affinity Lon binding sites present</p><br />
<br />
<br />
<br />
<br />
== Structural highlights ==<br />
<br />
== Evolutionary conservation ==<br />
<br />
The Lon proteolytic domain has a highly '''conserved structure'''. Like its orthologues, namely the eubacterium ''[https://fr.wikipedia.org/wiki/Escherichia_coli E. coli]'' (1rre), and the two archaea ''[https://en.wikipedia.org/wiki/Methanocaldococcus_jannaschii M. jannaschii]'' and ''[https://fr.wikipedia.org/wiki/Archaeoglobus_fulgidus A. fulgidus]'', it presents at its C-terminal a '''Ser-Lys dyad''' responsible of the substrate degradation activity. Although ''h''LonP active site resembles mostly to the one of ''Ec''LonP, the b5-sheet is replaced by an '''extension to a2'''. Thus, the N-terminal region of this helix carries the catalytic serine is a [https://en.wikipedia.org/wiki/310_helix 3(10) helix] and not a b-strand. As a consequence, ''h''LonP has the ability to bring the Asp852 into the active site to '''close''' it by forming a hydrogen bond with Lys898, a property already observed in ''Mj''Lon active site. This inactive state likely makes the catalytic serine inaccessible to the substrate and constraints the pKa of the lysine. Other main structural differences are '''loop shifts''' connecting the secondary structure elements b1 and b2, and a1.<br />
<br />
== Disease ==<br />
<br />
<p align="justify">Various [https://en.wikipedia.org/wiki/Myopathy myopathy], [https://en.wikipedia.org/wiki/Type_2_diabetes type 2 diabetes], [https://en.wikipedia.org/wiki/Parkinson%27s_disease Parkinson's disease], or [https://en.wikipedia.org/wiki/Alzheimer%27s_disease Alzheimer's disease] are human [https://en.wikipedia.org/wiki/Degenerative_disease degenerative disease] partly due to abnormalities of the mitochondria<ref>Wang, N, S Gottesman, M C Willingham, M M Gottesman, and M R Maurizi. “A Human Mitochondrial ATP-Dependent Protease That Is Highly Homologous to Bacterial Lon Protease.” Proceedings of the National Academy of Sciences 90, no. 23 (December 1, 1993): 11247–51. https://doi.org/10.1073/pnas.90.23.11247.<br />
</ref>. In fact, Lon protease has a role in [https://en.wikipedia.org/wiki/Cancer cancer], [https://en.wikipedia.org/wiki/Apoptosis apoptosis] and [https://en.wikipedia.org/wiki/Ageing aging] because this protein is an essential part of developmental pathways and stress response.<br />
<br><br />
[https://en.wikipedia.org/wiki/Mutant Mutant] in Lon decreases the degradation capacity of proteins with abnormal conformations which lead to mitochondrial dysfunction. Mitochondrial dysfunction causes normal cells to become apoptotic, or to aberrant adaptation and selection of hypoxic phenotypes in pathological conditions like cancer<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. <br />
<br><br />
Lon expression is necessary for survival in mammals. Indeed, a [https://en.wikipedia.org/wiki/Zygosity#Homozygous homozygous] [https://en.wikipedia.org/wiki/Deletion_(genetics) deletion] of LONP1 is lethal for early embryonic<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mhttps://proteopedia.org/wiki/skins/common/images/button_extlink.pngitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. Indeed, the [https://rarediseases.info.nih.gov/diseases/1418/codas-syndrome#:~:text=Summary,-Listen&text=Codas%20syndrome%20is%20a%20multiple,Dental%2C%20Auricular%20and%20Skeletal%20anomalies.&text=To%20date%2C%20three%20affected%20children,from%20Brazil)%20have%20been%20reported. CODAS Syndrome] is a rare and multi-system developmental disorder from heterozygous or homozygous mutations in LONP1 where all the affected children were very severely impacted by their disease.<br />
<br><br />
The LONP1 gene is regulated, when the cell undergoes a heat shock, [https://en.wikipedia.org/wiki/Starvation starvation] or oxidative stress the gene is up-regulated. On the contrary, Lon is down-regulated with aging, extensive [https://en.wikipedia.org/wiki/Hypoxia hypoxia], and prolonged oxidative stress. So Lon is an important factor in aging and degenerative disease. <br />
<br><br />
A [https://en.wikipedia.org/wiki/Consensus_sequence consensus] binding site of Nuclear Respiratory Factor 2 (NRF-2) is present on the region -623/+1 of the LONP1 promoter which is important for response to [https://en.wikipedia.org/wiki/Reactive_oxygen_species reactive oxygen species] related to oxidative stress. As well as the putative binding site in -2023/-1230 for [https://en.wikipedia.org/wiki/NF-%CE%BABhttps://en.wikipedia.org/wiki/NF-%CE%BAB NF-kB] in LONP1 which consolidate the role of Lon as a stress protein<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Lon Protease Preferentially Degrades Oxidized Mitochondrial Aconitase by an ATP-Stimulated Mechanism.” Nature Cell Biology 4, no. 9 (September 2002): 674–80. https://doi.org/10.1038/ncb836.</ref>. <br />
<br><br />
Research is being done to use Lon as a therapeutic target for the treatment of cancer by developing novel Lon inhibitors.</p><br />
<br />
<br />
<br><br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Rose Buhlmannhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1644&diff=3342084Sandbox Reserved 16442021-01-14T10:51:25Z<p>Rose Buhlmann: </p>
<hr />
<div>{{Sandbox_Reserved_ESBS20_}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==2x36 - Structure of the proteolytic domain of the <scene name='86/868177/Structure_hmlon_protease/1'>Human Mitochondrial Lon protease</scene>==<br />
<StructureSection load='2x36' size='340' side='right' caption='Structure of the Human Mitochondrial Lon protease' scene=''><br />
<br />
<p align="justify">'''2x36''' is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. This domain belongs to the [https://en.wikipedia.org/wiki/Lon_protease_family Lon protease family]. <br />
<br><br />
[https://en.wikipedia.org/wiki/Mitochondrion Mitochondrial] Lon [https://en.wikipedia.org/wiki/Protease protease] is an '''ATP-dependent serine protease''' involved '''in the selective degradation of abnormal proteins'''. [https://en.wikipedia.org/wiki/LONP1 LONP1] situated on chromosome 19 is the nuclear gene encoding mitochondrial Lon protein. The single species of [https://en.wikipedia.org/wiki/Messenger_RNA mRNA] of this protein is found in the mitochondrial matrix. This protein from human tissues has a molecular mass of 100 [https://en.wikipedia.org/wiki/Dalton_(unit) kDA].</p><br />
<br><br />
== Function ==<br />
<br />
<p align="justify">The mitochondrial Lon protease is an '''important regulator of mitochondrial [https://en.wikipedia.org/wiki/Metabolism metabolism]''' including the maintenance and repair of mitochondrial [https://en.wikipedia.org/wiki/DNA DNA]. This protein is also essential for '''homeostasis of mitochondria''', and by regulating some regulatory proteins which have '''a short life or damaged proteins'''. <br />
<br><br />
Lon protease has three main roles. <br />
This protein is able to do a '''[https://en.wikipedia.org/wiki/Proteolysis proteolytic] digestion''' of oxidized proteins which allows the renewal of essential mitochondrial enzymes such as [https://en.wikipedia.org/wiki/Aconitase aconitase] or [https://en.wikipedia.org/wiki/TFAM Mitochondrial transcription factor A].<br />
Lon protease is involved in [https://en.wikipedia.org/wiki/Mitochondrial_DNA mtDNA] [https://en.wikipedia.org/wiki/DNA_replication replication] and [https://en.wikipedia.org/w/index.php?title=Mitogenesis&redirect=no mitogenesis] by being a '''mitochondrial [https://en.wikipedia.org/wiki/DNA-binding_protein DNA-bing protein]'''. Human Lon and mtDNA associate at the level of their at least 4 contiguous [https://en.wikipedia.org/wiki/Guanine guanine] sequence and form '''a [https://en.wikipedia.org/wiki/G-quadruplex G-quadruplex]'''<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. This '''G-rich region''' is the control region for mtDNA replication and transcription<ref>Lu, Bin. “Mitochondrial Lon Protease and Cancer.” Advances in Experimental Medicine and Biology 1038 (2017): 173–82. https://doi.org/10.1007/978-981-10-6674-0_12.</ref>. <br />
<br><br />
Mitochondrial Lon protease interacts with '''[https://en.wikipedia.org/wiki/Chaperone_(protein) protein chaperone]''', notably [https://en.wikipedia.org/wiki/Chaperonin HSP60]-[https://en.wikipedia.org/wiki/Hsp70 Hsp70] complex to protect cell from apoptosis under environmental stress<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>.<br />
<br><br />
The mitochondrial Lon protease is essentially found in '''the cytoplasmic of mitochondria''' because [https://en.wikipedia.org/wiki/Amino_acid amino-acid] has a potential mitochondrial targetting presequences<ref>García-Nafría, Javier, Gabriela Ondrovičová, Elena Blagova, Vladimir M Levdikov, Jacob A Bauer, Carolyn K Suzuki, Eva Kutejová, Anthony J Wilkinson, and Keith S Wilson. “Structure of the Catalytic Domain of the Human Mitochondrial Lon Protease: Proposed Relation of Oligomer Formation and Activity.” Protein Science : A Publication of the Protein Society 19, no. 5 (May 2010): 987–99. https://doi.org/10.1002/pro.376.</ref>.<br />
<br><br />
Lon Human protease alternates between cycles of '''being bound to the mitochondrial genome''' and '''being free into the mitochondrial cytoplasm''' where it can degrade abnormal proteins coming from damaged proteins, errors in the synthesis, or [https://en.wikipedia.org/wiki/Protein_folding misfolded] of multimeric proteins. Its inactive conformation prevents '''uncontrolled proteolysis'''. <br />
To achieve proteolytic cleavage, the Lon protein has to form '''a hexamer'''. <br />
Lon protease has also a role in '''mtDNA quality control''' by permits oxidative mitochondrial DNA damage. Sensitivities of H2O2-induced mtDNA damage depend on the proportion of LON<ref>Lu, Bin. “Mitochondrial Lon Protease and Cancer.” Advances in Experimental Medicine and Biology 1038 (2017): 173–82. https://doi.org/10.1007/978-981-10-6674-0_12.</ref>. <br />
Other ATP-dependent proteases are found in eukaryotic cells and organelles like [https://en.wikipedia.org/wiki/Proteasome_endopeptidase_complex 26S protease] which uses [https://en.wikipedia.org/wiki/ATP_hydrolysis ATP hydrolysis] for conjugation or ubiquitin for example.</p><br />
<br><br />
<br />
== General structure ==<br />
<br />
<p align="justify">Lon proteins are grouped into two families, '''LonA''' and '''LonB'''. The human protein LonP1 is part of the LonA proteins <ref>« The N-terminal domain plays a crucial role in the structure of a full-length human mitochondrial Lon protease | Scientific Reports ». Consulté le 13 janvier 2021. https://www.nature.com/articles/srep33631.<br />
</ref>. This protein has three isoforms obtained by [https://en.wikipedia.org/wiki/Alternative_splicing alternative splicing] of the portion of DNA coding for this protein <ref>He, Lihong, Dongyang Luo, Fan Yang, Chunhao Li, Xuegong Zhang, Haiteng Deng, et Jing-Ren Zhang. « Multiple domains of bacterial and human Lon proteases define substrate selectivity ». Emerging Microbes & Infections 7 (17 août 2018). https://doi.org/10.1038/s41426-018-0148-4.<br />
</ref>.<br />
Globally there is a great diversity of Lon proteins, but they are all organised in an oligomeric ring structure, mostly hexameric structure with identical subunits.<br />
Lon proteins are therefore an hexameric chambered [https://en.wikipedia.org/wiki/Protease protease] complex. (This structure is similar with yeast [https://www.yeastgenome.org/locus/S000000118 Pim1] )<br />
The six Lon monomers are forming three pairs of legs owned by the N-terminal domain of the protein. This structure is emerging of the protein as a trimer of dimers <ref>Kutejová, Eva. « Mitochondrial Lon protease-unique structure and essential function in mammalian cells ». Integrative Cancer Science and Therapeutics 5, nᵒ 6 (2018). https://doi.org/10.15761/ICST.1000296.<br />
</ref>.<br />
<br><br />
Like many proteins, Lon is a '''flexible''' peptide which has different '''three-dimensional conformations'''. The protein can therefore pass from one conformation to another by hydrolysis of [https://biologydictionary.net/atp/ ATP]<ref>Voos, Wolfgang, et Karen Pollecker. « The Mitochondrial Lon Protease: Novel Functions off the Beaten Track? » Biomolecules 10, nᵒ 2 (7 février 2020). https://doi.org/10.3390/biom10020253.<br />
</ref>.<br />
With these conformational changes, the [https://en.wikipedia.org/wiki/Active_site '''active sites'''] of the Lon protein are protected from the external environment in the oligomeric complex that forms the '''degradation chamber'''.<br />
This form of degradation chamber is also found in bacteria, plants, fungi and metazoan, the similarities with bacteria are most probably due to the [https://en.wikipedia.org/wiki/Symbiogenesis endosymbiotic theory].<br />
<br><br />
<br><br />
This protein has a [https://en.wikipedia.org/wiki/Proteolysis '''proteolytic'''] and [https://en.wikipedia.org/wiki/Chaperone_(protein) '''chaperone''']-like activity, it cannot unfold aggregated proteins, but can participate in the assembling of some complexes). These two enzymatic activities are separated on two polypeptide chains forming a complex or two separate domains on the same polypeptide chain.<br />
<br><br />
The Lon protein has three main distinct domains: the first, the '''N-terminal''' domain, is specialised in '''substrate binding''' and [https://en.wikipedia.org/wiki/Oligomer '''oligomerization''']. The second, called the '''AAA+ domain''' (or A domain) corresponds to the fixation and hydrolysis site of the [https://biologydictionary.net/atp/ATP ATP]. Finally, the third domain located at the '''C-terminal''' is an active serine site leading to '''substrate degradation'''. This is a [https://en.wikipedia.org/wiki/Proteolysis '''proteolytic'''] domain, called domain P <ref>He, Lihong, Dongyang Luo, Fan Yang, Chunhao Li, Xuegong Zhang, Haiteng Deng, et Jing-Ren Zhang. « Multiple domains of bacterial and human Lon proteases define substrate selectivity ». Emerging Microbes & Infections 7 (17 août 2018). https://doi.org/10.1038/s41426-018-0148-4.<br />
</ref>.<br />
<br><br />
Mammalian Lon protein only interacts with '''single-stranded DNA''' (ssDNA) but not dsDNA. There are therefore special sequences for interaction with '''G-rich DNA''' as well as RNA. In addition, the binding of a substrate to the protein stimulates the interaction with the DNA.<br />
[https://en.wikipedia.org/wiki/Mitochondrial_DNA mtDNA] binds to the Lon protein with different affinities depending on the state of the cell and the type of cell meeting the following four parameters <ref>Lu, Bin, Swati Yadav, Parul G. Shah, Tong Liu, Bin Tian, Sebastian Pukszta, Nerissa Villaluna, et al. « Roles for the Human ATP-Dependent Lon Protease in Mitochondrial DNA Maintenance ». Journal of Biological Chemistry 282, nᵒ 24 (15 juin 2007): 17363‑74. https://doi.org/10.1074/jbc.M611540200.<br />
</ref>: <br />
<br><br />
- the single stranding state of mtDNA<br />
<br><br />
- the bioavailability of the mtDNA binding sites<br />
<br><br />
- the affinity of the protein for a given DNA sequence<br />
<br><br />
- the total number of high and low affinity Lon binding sites present</p><br />
<br />
<br />
<br />
<br />
== Structural highlights ==<br />
<br />
== Evolutionary conservation ==<br />
<br />
The Lon proteolytic domain has a highly conserved structure. Like its orthologues, namely the eubacterium E. coli (1rre), and the two archaea M. jannaschii and A. fulgidus, it presents at its C-terminal a Ser-Lys dyad responsible of the substrate degradation activity. Although hLonP active site resembles mostly to the one of EcLonP, the b5-sheet is replaced by an extension to a2. Thus, the N-terminal region of this helix carries the catalytic serine is a [https://en.wikipedia.org/wiki/310_helix 310 helix] and not a b-strand. As a consequence, hLonP has the ability to bring the Asp852 into the active site to close it by forming a hydrogen bond with Lys898, a property already observed in MjLon active site. This inactive state likely makes the catalytic serine inaccessible to the substrate and constraints the pKa of the lysine. Other main structure differences are loops shifts connecting the secondary structure elements b1 and b2, and a1.<br />
<br />
== Disease ==<br />
<br />
<p align="justify">Various [https://en.wikipedia.org/wiki/Myopathy myopathy], [https://en.wikipedia.org/wiki/Type_2_diabetes type 2 diabetes], [https://en.wikipedia.org/wiki/Parkinson%27s_disease Parkinson's disease], or [https://en.wikipedia.org/wiki/Alzheimer%27s_disease Alzheimer's disease] are human [https://en.wikipedia.org/wiki/Degenerative_disease degenerative disease] partly due to abnormalities of the mitochondria<ref>Wang, N, S Gottesman, M C Willingham, M M Gottesman, and M R Maurizi. “A Human Mitochondrial ATP-Dependent Protease That Is Highly Homologous to Bacterial Lon Protease.” Proceedings of the National Academy of Sciences 90, no. 23 (December 1, 1993): 11247–51. https://doi.org/10.1073/pnas.90.23.11247.<br />
</ref>. In fact, Lon protease has a role in [https://en.wikipedia.org/wiki/Cancer cancer], [https://en.wikipedia.org/wiki/Apoptosis apoptosis] and [https://en.wikipedia.org/wiki/Ageing aging] because this protein is an essential part of developmental pathways and stress response.<br />
<br><br />
[https://en.wikipedia.org/wiki/Mutant Mutant] in Lon decreases the degradation capacity of proteins with abnormal conformations which lead to mitochondrial dysfunction. Mitochondrial dysfunction causes normal cells to become apoptotic, or to aberrant adaptation and selection of hypoxic phenotypes in pathological conditions like cancer<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. <br />
<br><br />
Lon expression is necessary for survival in mammals. Indeed, a [https://en.wikipedia.org/wiki/Zygosity#Homozygous homozygous] [https://en.wikipedia.org/wiki/Deletion_(genetics) deletion] of LONP1 is lethal for early embryonic<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mhttps://proteopedia.org/wiki/skins/common/images/button_extlink.pngitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. Indeed, the [https://rarediseases.info.nih.gov/diseases/1418/codas-syndrome#:~:text=Summary,-Listen&text=Codas%20syndrome%20is%20a%20multiple,Dental%2C%20Auricular%20and%20Skeletal%20anomalies.&text=To%20date%2C%20three%20affected%20children,from%20Brazil)%20have%20been%20reported. CODAS Syndrome] is a rare and multi-system developmental disorder from heterozygous or homozygous mutations in LONP1 where all the affected children were very severely impacted by their disease.<br />
<br><br />
The LONP1 gene is regulated, when the cell undergoes a heat shock, [https://en.wikipedia.org/wiki/Starvation starvation] or oxidative stress the gene is up-regulated. On the contrary, Lon is down-regulated with aging, extensive [https://en.wikipedia.org/wiki/Hypoxia hypoxia], and prolonged oxidative stress. So Lon is an important factor in aging and degenerative disease. <br />
<br><br />
A [https://en.wikipedia.org/wiki/Consensus_sequence consensus] binding site of Nuclear Respiratory Factor 2 (NRF-2) is present on the region -623/+1 of the LONP1 promoter which is important for response to [https://en.wikipedia.org/wiki/Reactive_oxygen_species reactive oxygen species] related to oxidative stress. As well as the putative binding site in -2023/-1230 for [https://en.wikipedia.org/wiki/NF-%CE%BABhttps://en.wikipedia.org/wiki/NF-%CE%BAB NF-kB] in LONP1 which consolidate the role of Lon as a stress protein<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Lon Protease Preferentially Degrades Oxidized Mitochondrial Aconitase by an ATP-Stimulated Mechanism.” Nature Cell Biology 4, no. 9 (September 2002): 674–80. https://doi.org/10.1038/ncb836.</ref>. <br />
<br><br />
Research is being done to use Lon as a therapeutic target for the treatment of cancer by developing novel Lon inhibitors.</p><br />
<br />
<br />
<br><br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Rose Buhlmannhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1644&diff=3342061Sandbox Reserved 16442021-01-13T22:12:57Z<p>Rose Buhlmann: </p>
<hr />
<div>{{Sandbox_Reserved_ESBS20_}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==2x36 - Structure of the proteolytic domain of the <scene name='86/868177/Structure_hmlon_protease/1'>Human Mitochondrial Lon protease</scene>==<br />
<StructureSection load='2x36' size='340' side='right' caption='Structure of the Human Mitochondrial Lon protease' scene=''><br />
<br />
<p align="justify">'''2x36''' is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. This domain belongs to the [https://en.wikipedia.org/wiki/Lon_protease_family Lon protease family]. <br />
<br><br />
[https://en.wikipedia.org/wiki/Mitochondrion Mitochondrial] Lon [https://en.wikipedia.org/wiki/Protease protease] is an '''ATP-dependent serine protease''' involved in the selective degradation of abnormal proteins. [https://en.wikipedia.org/wiki/LONP1 LONP1] situated on chromosome 19 is the nuclear gene encoding mitochondrial Lon protein. The single species of [https://en.wikipedia.org/wiki/Messenger_RNA mRNA] of this protein is found in the mitochondrial matrix. This protein from human tissues has a molecular mass of 100 [https://en.wikipedia.org/wiki/Dalton_(unit) kDA].</p><br />
<br><br />
== Function ==<br />
<br />
<p align="justify">The mitochondrial Lon protease is an important regulator of mitochondrial [https://en.wikipedia.org/wiki/Metabolism metabolism] including the maintenance and repair of mitochondrial [https://en.wikipedia.org/wiki/DNA DNA]. This protein is also essential for homeostasis of mitochondria, and by regulating some regulatory proteins which have a short life or damaged proteins. <br />
<br><br />
Lon protease has three main roles. <br />
This protein is able to do a '''[https://en.wikipedia.org/wiki/Proteolysis proteolytic] digestion''' of oxidized proteins which allows the renewal of essential mitochondrial enzymes such as [https://en.wikipedia.org/wiki/Aconitase aconitase] or [https://en.wikipedia.org/wiki/TFAM Mitochondrial transcription factor A].<br />
Lon protease is involved in [https://en.wikipedia.org/wiki/Mitochondrial_DNA mtDNA] [https://en.wikipedia.org/wiki/DNA_replication replication] and [https://en.wikipedia.org/w/index.php?title=Mitogenesis&redirect=no mitogenesis] by being a '''mitochondrial [https://en.wikipedia.org/wiki/DNA-binding_protein DNA-bing protein]'''. Human Lon and mtDNA associate at the level of their at least 4 contiguous [https://en.wikipedia.org/wiki/Guanine guanine] sequence and form a [https://en.wikipedia.org/wiki/G-quadruplex G-quadruplex]<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. This G-rich region is the control region for mtDNA replication and transcription<ref>Lu, Bin. “Mitochondrial Lon Protease and Cancer.” Advances in Experimental Medicine and Biology 1038 (2017): 173–82. https://doi.org/10.1007/978-981-10-6674-0_12.</ref>. <br />
<br><br />
Mitochondrial Lon protease interacts with '''[https://en.wikipedia.org/wiki/Chaperone_(protein) protein chaperone]''', notably [https://en.wikipedia.org/wiki/Chaperonin HSP60]-[https://en.wikipedia.org/wiki/Hsp70 Hsp70] complex to protect cell from apoptosis under environmental stress<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>.<br />
<br><br />
The mitochondrial Lon protease is essentially found in the cytoplasmic of mitochondria because [https://en.wikipedia.org/wiki/Amino_acid amino-acid] has a potential mitochondrial targetting presequences<ref>García-Nafría, Javier, Gabriela Ondrovičová, Elena Blagova, Vladimir M Levdikov, Jacob A Bauer, Carolyn K Suzuki, Eva Kutejová, Anthony J Wilkinson, and Keith S Wilson. “Structure of the Catalytic Domain of the Human Mitochondrial Lon Protease: Proposed Relation of Oligomer Formation and Activity.” Protein Science : A Publication of the Protein Society 19, no. 5 (May 2010): 987–99. https://doi.org/10.1002/pro.376.</ref>.<br />
<br><br />
Lon Human protease alternates between cycles of '''being bound to the mitochondrial genome''' and '''being free into the mitochondrial cytoplasm''' where it can degrade abnormal proteins coming from damaged proteins, errors in the synthesis, or [https://en.wikipedia.org/wiki/Protein_folding misfolded] of multimeric proteins. Its inactive conformation prevents uncontrolled proteolysis. <br />
To achieve proteolytic cleavage, the Lon protein has to form a hexamer. <br />
Lon protease has also a role in mtDNA quality control by permits oxidative mitochondrial DNA damage. Sensitivities of H2O2-induced mtDNA damage depend on the proportion of LON<ref>Lu, Bin. “Mitochondrial Lon Protease and Cancer.” Advances in Experimental Medicine and Biology 1038 (2017): 173–82. https://doi.org/10.1007/978-981-10-6674-0_12.</ref>. <br />
Other ATP-dependent proteases are found in eukaryotic cells and organelles like [https://en.wikipedia.org/wiki/Proteasome_endopeptidase_complex 26S protease] which uses [https://en.wikipedia.org/wiki/ATP_hydrolysis ATP hydrolysis] for conjugation or ubiquitin for example.</p><br />
<br><br />
<br />
== General structure ==<br />
<br />
<p align="justify">Lon proteins are grouped into two families, '''LonA''' and '''LonB'''. The human protein LonP1 is part of the LonA proteins <ref>« The N-terminal domain plays a crucial role in the structure of a full-length human mitochondrial Lon protease | Scientific Reports ». Consulté le 13 janvier 2021. https://www.nature.com/articles/srep33631.<br />
</ref>. This protein has three isoforms obtained by [https://en.wikipedia.org/wiki/Alternative_splicing alternative splicing] of the portion of DNA coding for this protein <ref>He, Lihong, Dongyang Luo, Fan Yang, Chunhao Li, Xuegong Zhang, Haiteng Deng, et Jing-Ren Zhang. « Multiple domains of bacterial and human Lon proteases define substrate selectivity ». Emerging Microbes & Infections 7 (17 août 2018). https://doi.org/10.1038/s41426-018-0148-4.<br />
</ref>.<br />
Globally there is a great diversity of Lon proteins, but they are all organised in an oligomeric ring structure, mostly hexameric structure with identical subunits.<br />
Lon proteins are therefore an hexameric chambered [https://en.wikipedia.org/wiki/Protease protease] complex. (This structure is similar with yeast [https://www.yeastgenome.org/locus/S000000118 Pim1] )<br />
The six Lon monomers are forming three pairs of legs owned by the N-terminal domain of the protein. This structure is emerging of the protein as a trimer of dimers <ref>Kutejová, Eva. « Mitochondrial Lon protease-unique structure and essential function in mammalian cells ». Integrative Cancer Science and Therapeutics 5, nᵒ 6 (2018). https://doi.org/10.15761/ICST.1000296.<br />
</ref>.<br />
<br><br />
Like many proteins, Lon is a '''flexible''' peptide which has different '''three-dimensional conformations'''. The protein can therefore pass from one conformation to another by hydrolysis of [https://biologydictionary.net/atp/ ATP]<ref>Voos, Wolfgang, et Karen Pollecker. « The Mitochondrial Lon Protease: Novel Functions off the Beaten Track? » Biomolecules 10, nᵒ 2 (7 février 2020). https://doi.org/10.3390/biom10020253.<br />
</ref>.<br />
With these conformational changes, the [https://en.wikipedia.org/wiki/Active_site '''active sites'''] of the Lon protein are protected from the external environment in the oligomeric complex that forms the '''degradation chamber'''.<br />
This form of degradation chamber is also found in bacteria, plants, fungi and metazoan, the similarities with bacteria are most probably due to the [https://en.wikipedia.org/wiki/Symbiogenesis endosymbiotic theory].<br />
<br><br />
<br><br />
This protein has a [https://en.wikipedia.org/wiki/Proteolysis '''proteolytic'''] and [https://en.wikipedia.org/wiki/Chaperone_(protein) '''chaperone''']-like activity, it cannot unfold aggregated proteins, but can participate in the assembling of some complexes). These two enzymatic activities are separated on two polypeptide chains forming a complex or two separate domains on the same polypeptide chain.<br />
<br><br />
The Lon protein has three main distinct domains: the first, the '''N-terminal''' domain, is specialised in '''substrate binding''' and [https://en.wikipedia.org/wiki/Oligomer '''oligomerization''']. The second, called the '''AAA+ domain''' (or A domain) corresponds to the fixation and hydrolysis site of the [https://biologydictionary.net/atp/ATP ATP]. Finally, the third domain located at the '''C-terminal''' is an active serine site leading to '''substrate degradation'''. This is a [https://en.wikipedia.org/wiki/Proteolysis '''proteolytic'''] domain, called domain P <ref>He, Lihong, Dongyang Luo, Fan Yang, Chunhao Li, Xuegong Zhang, Haiteng Deng, et Jing-Ren Zhang. « Multiple domains of bacterial and human Lon proteases define substrate selectivity ». Emerging Microbes & Infections 7 (17 août 2018). https://doi.org/10.1038/s41426-018-0148-4.<br />
</ref>.<br />
<br><br />
Mammalian Lon protein only interacts with '''single-stranded DNA''' (ssDNA) but not dsDNA. There are therefore special sequences for interaction with '''G-rich DNA''' as well as RNA. In addition, the binding of a substrate to the protein stimulates the interaction with the DNA.<br />
[https://en.wikipedia.org/wiki/Mitochondrial_DNA mtDNA] binds to the Lon protein with different affinities depending on the state of the cell and the type of cell meeting the following four parameters <ref>Lu, Bin, Swati Yadav, Parul G. Shah, Tong Liu, Bin Tian, Sebastian Pukszta, Nerissa Villaluna, et al. « Roles for the Human ATP-Dependent Lon Protease in Mitochondrial DNA Maintenance ». Journal of Biological Chemistry 282, nᵒ 24 (15 juin 2007): 17363‑74. https://doi.org/10.1074/jbc.M611540200.<br />
</ref>: <br />
<br><br />
- the single stranding state of mtDNA<br />
<br><br />
- the bioavailability of the mtDNA binding sites<br />
<br><br />
- the affinity of the protein for a given DNA sequence<br />
<br><br />
- the total number of high and low affinity Lon binding sites present</p><br />
<br />
<br />
<br />
<br />
== Structural highlights ==<br />
<br />
== Evolutionary conservation ==<br />
<br />
The Lon proteolytic domain has a highly conserved structure. Like its orthologues, namely the eubacterium E. coli (1rre), and the two archaea M. jannaschii and A. fulgidus, it presents at its C-terminal a Ser-Lys dyad responsible of the substrate degradation activity. Although hLonP active site resembles mostly to the one of EcLonP, the b5-sheet is replaced by an extension to a2. Thus, the N-terminal region of this helix carries the catalytic serine is a 310 helix and not a b-strand. As a consequence, hLonP has the ability to bring the Asp852 into the active site to close it by forming a hydrogen bond with Lys898, a property already observed in MjLon active site. This inactive state likely makes the catalytic serine inaccessible to the substrate and constraints the pKa of the lysine. Other main structure differences are loops shifts connecting the secondary structure elements b1 and b2, and a1.<br />
<br />
== Disease ==<br />
<br />
<p align="justify">Various [https://en.wikipedia.org/wiki/Myopathy myopathy], [https://en.wikipedia.org/wiki/Type_2_diabetes type 2 diabetes], [https://en.wikipedia.org/wiki/Parkinson%27s_disease Parkinson's disease], or [https://en.wikipedia.org/wiki/Alzheimer%27s_disease Alzheimer's disease] are human [https://en.wikipedia.org/wiki/Degenerative_disease degenerative disease] partly due to abnormalities of the mitochondria<ref>Wang, N, S Gottesman, M C Willingham, M M Gottesman, and M R Maurizi. “A Human Mitochondrial ATP-Dependent Protease That Is Highly Homologous to Bacterial Lon Protease.” Proceedings of the National Academy of Sciences 90, no. 23 (December 1, 1993): 11247–51. https://doi.org/10.1073/pnas.90.23.11247.<br />
</ref>. In fact, Lon protease has a role in [https://en.wikipedia.org/wiki/Cancer cancer], [https://en.wikipedia.org/wiki/Apoptosis apoptosis] and [https://en.wikipedia.org/wiki/Ageing aging] because this protein is an essential part of developmental pathways and stress response.<br />
<br><br />
[https://en.wikipedia.org/wiki/Mutant Mutant] in Lon decreases the degradation capacity of proteins with abnormal conformations which lead to mitochondrial dysfunction. Mitochondrial dysfunction causes normal cells to become apoptotic, or to aberrant adaptation and selection of hypoxic phenotypes in pathological conditions like cancer<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. <br />
<br><br />
Lon expression is necessary for survival in mammals. Indeed, a [https://en.wikipedia.org/wiki/Zygosity#Homozygous homozygous] [https://en.wikipedia.org/wiki/Deletion_(genetics) deletion] of LONP1 is lethal for early embryonic<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mhttps://proteopedia.org/wiki/skins/common/images/button_extlink.pngitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. Indeed, the [https://rarediseases.info.nih.gov/diseases/1418/codas-syndrome#:~:text=Summary,-Listen&text=Codas%20syndrome%20is%20a%20multiple,Dental%2C%20Auricular%20and%20Skeletal%20anomalies.&text=To%20date%2C%20three%20affected%20children,from%20Brazil)%20have%20been%20reported. CODAS Syndrome] is a rare and multi-system developmental disorder from heterozygous or homozygous mutations in LONP1 where all the affected children were very severely impacted by their disease.<br />
<br><br />
The LONP1 gene is regulated, when the cell undergoes a heat shock, [https://en.wikipedia.org/wiki/Starvation starvation] or oxidative stress the gene is up-regulated. On the contrary, Lon is down-regulated with aging, extensive [https://en.wikipedia.org/wiki/Hypoxia hypoxia], and prolonged oxidative stress. So Lon is an important factor in aging and degenerative disease. <br />
<br><br />
A [https://en.wikipedia.org/wiki/Consensus_sequence consensus] binding site of Nuclear Respiratory Factor 2 (NRF-2) is present on the region -623/+1 of the LONP1 promoter which is important for response to [https://en.wikipedia.org/wiki/Reactive_oxygen_species reactive oxygen species] related to oxidative stress. As well as the putative binding site in -2023/-1230 for [https://en.wikipedia.org/wiki/NF-%CE%BABhttps://en.wikipedia.org/wiki/NF-%CE%BAB NF-kB] in LONP1 which consolidate the role of Lon as a stress protein<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Lon Protease Preferentially Degrades Oxidized Mitochondrial Aconitase by an ATP-Stimulated Mechanism.” Nature Cell Biology 4, no. 9 (September 2002): 674–80. https://doi.org/10.1038/ncb836.</ref>. <br />
<br><br />
Research is being done to use Lon as a therapeutic target for the treatment of cancer by developing novel Lon inhibitors.</p><br />
<br />
<br />
<br><br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Rose Buhlmannhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1644&diff=3341954Sandbox Reserved 16442021-01-13T18:46:49Z<p>Rose Buhlmann: </p>
<hr />
<div>{{Sandbox_Reserved_ESBS20_}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==2x36 - Structure of the proteolytic domain of the <scene name='86/868177/Structure_hmlon_protease/1'>Human Mitochondrial Lon protease</scene>==<br />
<StructureSection load='2x36' size='340' side='right' caption='Structure of the Human Mitochondrial Lon protease' scene=''><br />
<br />
<p align="justify">'''2x36''' is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. This domain belongs to the [https://en.wikipedia.org/wiki/Lon_protease_family Lon protease family]. <br />
<br><br />
[https://en.wikipedia.org/wiki/Mitochondrion Mitochondrial] Lon [https://en.wikipedia.org/wiki/Protease protease] is an '''ATP-dependent serine protease''' involved in the selective degradation of abnormal proteins. [https://en.wikipedia.org/wiki/LONP1 LONP1] situated on chromosome 19 is the nuclear gene encoding mitochondrial Lon protein. The single species of [https://en.wikipedia.org/wiki/Messenger_RNA mRNA] of this protein is found in the mitochondrial matrix. This protein from human tissues has a molecular mass of 100 [https://en.wikipedia.org/wiki/Dalton_(unit) kDA].</p><br />
<br><br />
== Function ==<br />
<br />
<p align="justify">The mitochondrial Lon protease is an important regulator of mitochondrial [https://en.wikipedia.org/wiki/Metabolism metabolism] including the maintenance and repair of mitochondrial [https://en.wikipedia.org/wiki/DNA DNA]. This protein is also essential for homeostasis of mitochondria, and by regulating some regulatory proteins which have a short life or damaged proteins. <br />
<br><br />
Lon protease has three main roles. <br />
This protein is able to do a '''[https://en.wikipedia.org/wiki/Proteolysis proteolytic] digestion''' of oxidized proteins which allows the renewal of essential mitochondrial enzymes such as [https://en.wikipedia.org/wiki/Aconitase aconitase] or [https://en.wikipedia.org/wiki/TFAM Mitochondrial transcription factor A].<br />
Lon protease is involved in [https://en.wikipedia.org/wiki/Mitochondrial_DNA mtDNA] [https://en.wikipedia.org/wiki/DNA_replication replication] and [https://en.wikipedia.org/w/index.php?title=Mitogenesis&redirect=no mitogenesis] by being a '''mitochondrial [https://en.wikipedia.org/wiki/DNA-binding_protein DNA-bing protein]'''. Human Lon and mtDNA associate at the level of their at least 4 contiguous [https://en.wikipedia.org/wiki/Guanine guanine] sequence and form a [https://en.wikipedia.org/wiki/G-quadruplex G-quadruplex]<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. This G-rich region is the control region for mtDNA replication and transcription<ref>Lu, Bin. “Mitochondrial Lon Protease and Cancer.” Advances in Experimental Medicine and Biology 1038 (2017): 173–82. https://doi.org/10.1007/978-981-10-6674-0_12.</ref>. <br />
<br><br />
Mitochondrial Lon protease interacts with '''[https://en.wikipedia.org/wiki/Chaperone_(protein) protein chaperone]''', notably [https://en.wikipedia.org/wiki/Chaperonin HSP60]-[https://en.wikipedia.org/wiki/Hsp70 Hsp70] complex to protect cell from apoptosis under environmental stress<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>.<br />
<br><br />
The mitochondrial Lon protease is essentially found in the cytoplasmic of mitochondria because [https://en.wikipedia.org/wiki/Amino_acid amino-acid] has a potential mitochondrial targetting presequences<ref>García-Nafría, Javier, Gabriela Ondrovičová, Elena Blagova, Vladimir M Levdikov, Jacob A Bauer, Carolyn K Suzuki, Eva Kutejová, Anthony J Wilkinson, and Keith S Wilson. “Structure of the Catalytic Domain of the Human Mitochondrial Lon Protease: Proposed Relation of Oligomer Formation and Activity.” Protein Science : A Publication of the Protein Society 19, no. 5 (May 2010): 987–99. https://doi.org/10.1002/pro.376.</ref>.<br />
<br><br />
Lon Human protease alternates between cycles of '''being bound to the mitochondrial genome''' and '''being free into the mitochondrial cytoplasm''' where it can degrade abnormal proteins coming from damaged proteins, errors in the synthesis, or [https://en.wikipedia.org/wiki/Protein_folding misfolded] of multimeric proteins. Its inactive conformation prevents uncontrolled proteolysis. <br />
To achieve proteolytic cleavage, the Lon protein has to form a hexamer. <br />
Lon protease has also a role in mtDNA quality control by permits oxidative mitochondrial DNA damage. Sensitivities of H2O2-induced mtDNA damage depend on the proportion of LON<ref>Lu, Bin. “Mitochondrial Lon Protease and Cancer.” Advances in Experimental Medicine and Biology 1038 (2017): 173–82. https://doi.org/10.1007/978-981-10-6674-0_12.</ref>. <br />
Other ATP-dependent proteases are found in eukaryotic cells and organelles like [https://en.wikipedia.org/wiki/Proteasome_endopeptidase_complex 26S protease] which uses [https://en.wikipedia.org/wiki/ATP_hydrolysis ATP hydrolysis] for conjugation or ubiquitin for example.</p><br />
<br><br />
<br />
== General structure ==<br />
<br />
<p align="justify">Lon proteins are grouped into two families, '''LonA''' and '''LonB'''. The human protein LonP1 is part of the LonA proteins <ref>« The N-terminal domain plays a crucial role in the structure of a full-length human mitochondrial Lon protease | Scientific Reports ». Consulté le 13 janvier 2021. https://www.nature.com/articles/srep33631.<br />
</ref>. This protein has three isoforms obtained by [https://en.wikipedia.org/wiki/Alternative_splicing alternative splicing] of the portion of DNA coding for this protein <ref>He, Lihong, Dongyang Luo, Fan Yang, Chunhao Li, Xuegong Zhang, Haiteng Deng, et Jing-Ren Zhang. « Multiple domains of bacterial and human Lon proteases define substrate selectivity ». Emerging Microbes & Infections 7 (17 août 2018). https://doi.org/10.1038/s41426-018-0148-4.<br />
</ref>.<br />
Globally there is a great diversity of Lon proteins, but they are all organised in an oligomeric ring structure, mostly hexameric structure with identical subunits.<br />
Lon proteins are therefore an hexameric chambered [https://en.wikipedia.org/wiki/Protease protease] complex. (This structure is similar with yeast [https://www.yeastgenome.org/locus/S000000118 Pim1] )<br />
The six Lon monomers are forming three pairs of legs owned by the N-terminal domain of the protein. This structure is emerging of the protein as a trimer of dimers <ref>Kutejová, Eva. « Mitochondrial Lon protease-unique structure and essential function in mammalian cells ». Integrative Cancer Science and Therapeutics 5, nᵒ 6 (2018). https://doi.org/10.15761/ICST.1000296.<br />
</ref>.<br />
<br><br />
Like many proteins, Lon is a '''flexible''' peptide which has different '''three-dimensional conformations'''. The protein can therefore pass from one conformation to another by hydrolysis of [https://biologydictionary.net/atp/ ATP]<ref>Voos, Wolfgang, et Karen Pollecker. « The Mitochondrial Lon Protease: Novel Functions off the Beaten Track? » Biomolecules 10, nᵒ 2 (7 février 2020). https://doi.org/10.3390/biom10020253.<br />
</ref>.<br />
With these conformational changes, the [https://en.wikipedia.org/wiki/Active_site '''active sites'''] of the Lon protein are protected from the external environment in the oligomeric complex that forms the '''degradation chamber'''.<br />
This form of degradation chamber is also found in bacteria, plants, fungi and metazoan, the similarities with bacteria are most probably due to the [https://en.wikipedia.org/wiki/Symbiogenesis endosymbiotic theory].<br />
<br><br />
<br><br />
This protein has a [https://en.wikipedia.org/wiki/Proteolysis '''proteolytic'''] and [https://en.wikipedia.org/wiki/Chaperone_(protein) '''chaperone''']-like activity, it cannot unfold aggregated proteins, but can participate in the assembling of some complexes). These two enzymatic activities are separated on two polypeptide chains forming a complex or two separate domains on the same polypeptide chain.<br />
<br><br />
The Lon protein has three main distinct domains: the first, the '''N-terminal''' domain, is specialised in '''substrate binding''' and [https://en.wikipedia.org/wiki/Oligomer '''oligomerization''']. The second, called the '''AAA+ domain''' (or A domain) corresponds to the fixation and hydrolysis site of the [https://biologydictionary.net/atp/ATP ATP]. Finally, the third domain located at the '''C-terminal''' is an active serine site leading to '''substrate degradation'''. This is a [https://en.wikipedia.org/wiki/Proteolysis '''proteolytic'''] domain, called domain P <ref>He, Lihong, Dongyang Luo, Fan Yang, Chunhao Li, Xuegong Zhang, Haiteng Deng, et Jing-Ren Zhang. « Multiple domains of bacterial and human Lon proteases define substrate selectivity ». Emerging Microbes & Infections 7 (17 août 2018). https://doi.org/10.1038/s41426-018-0148-4.<br />
</ref>.<br />
<br><br />
Mammalian Lon protein only interacts with '''single-stranded DNA''' (ssDNA) but not dsDNA. There are therefore special sequences for interaction with '''G-rich DNA''' as well as RNA. In addition, the binding of a substrate to the protein stimulates the interaction with the DNA.<br />
[https://en.wikipedia.org/wiki/Mitochondrial_DNA mtDNA] binds to the Lon protein with different affinities depending on the state of the cell and the type of cell meeting the following four parameters <ref>Lu, Bin, Swati Yadav, Parul G. Shah, Tong Liu, Bin Tian, Sebastian Pukszta, Nerissa Villaluna, et al. « Roles for the Human ATP-Dependent Lon Protease in Mitochondrial DNA Maintenance ». Journal of Biological Chemistry 282, nᵒ 24 (15 juin 2007): 17363‑74. https://doi.org/10.1074/jbc.M611540200.<br />
</ref>: <br />
<br><br />
- the single stranding state of mtDNA<br />
<br><br />
- the bioavailability of the mtDNA binding sites<br />
<br><br />
- the affinity of the protein for a given DNA sequence<br />
<br><br />
- the total number of high and low affinity Lon binding sites present</p><br />
<br />
<br />
<br />
<br />
== Structural highlights ==<br />
<br />
== Evolutionary conservation ==<br />
<br />
== Disease ==<br />
<br />
<p align="justify">Various [https://en.wikipedia.org/wiki/Myopathy myopathy], [https://en.wikipedia.org/wiki/Type_2_diabetes type 2 diabetes], [https://en.wikipedia.org/wiki/Parkinson%27s_disease Parkinson's disease], or [https://en.wikipedia.org/wiki/Alzheimer%27s_disease Alzheimer's disease] are human [https://en.wikipedia.org/wiki/Degenerative_disease degenerative disease] partly due to abnormalities of the mitochondria<ref>Wang, N, S Gottesman, M C Willingham, M M Gottesman, and M R Maurizi. “A Human Mitochondrial ATP-Dependent Protease That Is Highly Homologous to Bacterial Lon Protease.” Proceedings of the National Academy of Sciences 90, no. 23 (December 1, 1993): 11247–51. https://doi.org/10.1073/pnas.90.23.11247.<br />
</ref>. In fact, Lon protease has a role in [https://en.wikipedia.org/wiki/Cancer cancer], [https://en.wikipedia.org/wiki/Apoptosis apoptosis] and [https://en.wikipedia.org/wiki/Ageing aging] because this protein is an essential part of developmental pathways and stress response.<br />
<br><br />
[https://en.wikipedia.org/wiki/Mutant Mutant] in Lon decreases the degradation capacity of proteins with abnormal conformations which lead to mitochondrial dysfunction. Mitochondrial dysfunction causes normal cells to become apoptotic, or to aberrant adaptation and selection of hypoxic phenotypes in pathological conditions like cancer<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>. <br />
<br><br />
Lon expression is necessary for survival in mammals. Indeed, a [https://en.wikipedia.org/wiki/Zygosity#Homozygous homozygous] [https://en.wikipedia.org/wiki/Deletion_(genetics) deletion] of LONP1 is lethal for early embryonic<ref>Bota, Daniela A., and Kelvin J. A. Davies. “Mhttps://proteopedia.org/wiki/skins/common/images/button_extlink.pngitochondrial Lon Protease in Human Disease and Aging: Including an Etiologic Classification of Lon-Related Diseases and Disorders.” Free Radical Biology & Medicine 100 (November 2016): 188–98. https://doi.org/10.1016/j.freeradbiomed.2016.06.031.</ref>.<br />
<br><br />
The LONP1 gene is regulated, when the cell undergoes a heat shock, [https://en.wikipedia.org/wiki/Starvation starvation] or oxidative stress the gene is up-regulated. On the contrary, Lon is down-regulated with aging, extensive [https://en.wikipedia.org/wiki/Hypoxia hypoxia], and prolonged oxidative stress. So Lon is an important factor in aging and degenerative disease. <br />
<br><br />
A [https://en.wikipedia.org/wiki/Consensus_sequence consensus] binding site of Nuclear Respiratory Factor 2 (NRF-2) is present on the region -623/+1 of the LONP1 promoter which is important for response to [https://en.wikipedia.org/wiki/Reactive_oxygen_species reactive oxygen species] related to oxidative stress. <br />
<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
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<hr />
<div>{{Sandbox_Reserved_ESBS20_}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Cytoplasmic Polyadenylation Element-Binding Protein (CPEB)==<br />
[https://en.wikipedia.org/wiki/CPEB CPEB ](Cytoplasmic polyadenylation element binding protein) is present in most vertebrates and invertebrates and can activate or inhibit translation, depending on the different factors it can bind<ref>DOI 10.1016/j.tibs.2007.04.004</ref>. In human body there are 4 different isoforms of CPEB ([https://en.wikipedia.org/wiki/CPEB1 CPEB1] to CPEB4), distributed throughout body in a tissue-dependent manner and which interact differently with mRNA<ref name="publi">DOI 10.1016/j.arr.2012.03.004</ref>.<br />
CPEB protein regulates the length of the polyA tail which allows to control the translation. It binds to mRNA and in association with some factors, can act as a translational repressor or activator, depending on these factors.<br />
<br />
== Structure ==<br />
All CPEB proteins have a similar structure :<br />
* A N-terminal region which is a regulatory region with phosphorylation and dephosphorylation sites. This region is variable in length and composition.<br />
* A C-terminal region, composed of 2 recognition patterns : RRMs domains and zinc finger domains.<br />
** '''Zinc finger patterns'''<ref>DOI 10.1016/j.jmb.2013.03.009</ref><br />
<StructureSection load='2m13' size='340' side='left' caption='Caption for this structure' scene=''><br />
</StructureSection><br />
About 54 residues with 6 cysteines and 2 histidines involved in a bond with a zinc atom, conserved for all isoforms and species. The modification of one of the eight zinc ligands destabilize the connection to the mRNA. <scene name='86/868187/Zz/3'>The domain</scene> includes :<br />
***A <scene name='86/868187/Rd_turn/1'>Rubredoxin turn</scene> (Rd turn, residues 515-520), which is stabilized by hydrogen bonds between amide and sulfure.<br />
***β-hairpin with <scene name='86/868187/B1/1'>β1</scene> (residues 525-527) and <scene name='86/868187/B2/1'>β2</scene> (residues 533-535) between which there is an helical turn stabilized by hydrogen bonds.<br />
***An <scene name='86/868187/A/1'>α1 helix</scene> (residues 538-545) which forms the second bridge between the two zinc-binding sites. The surface-exposed face of the helix has a potential for specific intermolecular interactions with nucleic acids or proteins.<br />
***A 3<sub>10</sub> <scene name='86/868187/310/1'> helical turn</scene> (residues 550-552).<br />
***2 zinc binding sites, the first one is composed of <scene name='86/868187/Z1/3'>Cys515, Cys518, Cys537, Cys540</scene> and the second is composed of <scene name='86/868187/Z2/2'>Cys527, Cys532, His545 and His553</scene>.<br />
** '''RRMs patterns'''<ref>DOI 10.1101/gad.241133.114</ref><br />
<StructureSection load='2MKK' size='350' side='right' caption='RNA binding to RRM' scene=''><br />
</StructureSection><br />
RRMs are necessary and sufficient for the CPE sequence recognition on RNA. They bind to RNA with high affinity and allow the RNA to take the good position. RRM1 binds to the four first RNA nucleotides (UUUU) and RRM2 binds to the 3' adenine of CPE. The two RRMs take a V-shaped conformation, facing to each other:<br />
***RRM1 has anti-parallel beta strands between the alpha helix and the beta4 strand.<br />
***The interdomain linker takes a helical turn that interacts with residues of the N-terminal extension and with RRM2.<br />
***<scene name='86/868187/Rmm/1'>Trp331</scene> positions RRM2 relative to RRM1 by inserting its indole ring between the beta sheet and alpha1 helix of RRM2. <br />
***After the helical turn, the interdomain linker folds in a beta strand which is anti-parallel to the beta2 strand (RRM2). The interdomain linker is therefore a kind of joint for the relative orientation of the two RRMs.<br />
<br />
== Function ==<br />
CPEB controls the balance between [https://en.wikipedia.org/wiki/Senescence senescence] and proliferation. Indeed, due to its two structural domains in its C-terminal region, it has the capacity to modify mRNA<ref name="publi" />.<br />
RRMs domains allow binding to the [https://en.wikipedia.org/wiki/Cytoplasmic_polyadenylation_element CPE] sequence of mRNA (pyrimidine rich : UUUUUAU), thus ensuring good RNA positioning and high fidelity.<br />
Zing finger domains allow binding to different proteins, which play a role in affinity but not in specificity. It's therefore its ability to recruit different proteins that will determine its action, activation or repression of translation.<br />
<br />
A specific arrangement of CPEs in mRNA can lead to the repression of the translation. In this case, the CPEB can form a dimer which could avoid the bound of the polyA polymerase complex in 2 different ways. It could prevent the association of ePAB with the polyA tail because CPEB recruits the deadenylase [https://en.wikipedia.org/wiki/Poly(A)-specific_ribonuclease PARN] which reduce the length of the polyA tail. It could disrupt the interaction between the binding factors of the translation [https://en.wikipedia.org/wiki/EIF4E eIF4E] and [https://en.wikipedia.org/wiki/EIF4G eIF4G] too, because CPEB recruits the protein Maskin which blocks eIF4G recruitment too<ref name="publi" />. This prevents the bound of the cap machinery to the mRNA and therefore inhibits the translation.<br />
<br />
On the other hand, the CPEB can activate the translation. Indeed, in the cytoplasm, there are some repressed or silenced mRNA with a short polyA tail. They can be activated by cytoplasmic polyadenylation thanks to a hormonal stimulation. This stimulation can lead to the phosphorylation of CPEB which increase its affinity with the [https://en.m.wikipedia.org/wiki/Cleavage_and_polyadenylation_specificity_factor CPSF] (Cleavage and Polyadenylation Specificity Factor) and decrease the binding between CPEB and PARN. CPSF binds to the mRNA at the sequence 3’ of the tail of the mRNA (AAUAAA) and recruits the [https://en.wikipedia.org/wiki/Polynucleotide_adenylyltransferase poly(A) polymerase] which leads to the elongation of the polyA tail and therefore to the activation of the translation<ref name="publi" />. <br />
<br />
<br />
== Disease ==<br />
<br />
<br />
== References ==<br />
<references/></div>Rose Buhlmannhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1654&diff=3341195Sandbox Reserved 16542021-01-09T18:29:46Z<p>Rose Buhlmann: </p>
<hr />
<div>{{Sandbox_Reserved_ESBS20_}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Cytoplasmic Polyadenylation Element-Binding Protein (CPEB)==<br />
[https://en.wikipedia.org/wiki/CPEB CPEB ](Cytoplasmic polyadenylation element binding protein) is present in most vertebrates and invertebrates and can activate or inhibit translation. In human body, there are 4 different isoforms of CPEB (CPEB1, CPEB2, CPEB3, CPEB4), which interact differently with mRNA. <br />
<br />
== Structure ==<br />
All CPEB proteins have a similar structure :<br />
* A N-terminal region which is a regulatory region with phosphorylation and dephosphorylation sites. This region is variable in length and composition.<br />
* A C-terminal region, composed of 2 recognition patterns : RRMs domains and zinc finger domains.<br />
** '''Zinc finger patterns''' <ref>DOI 10.1016/j.jmb.2013.03.009</ref><br />
<StructureSection load='2m13' size='340' side='left' caption='Caption for this structure' scene=''><br />
</StructureSection><br />
About 54 residues with 6 cysteines and 2 histidines involved in a bond with a zinc atom, conserved for all isoforms and species. The modification of one of the eight zinc ligands destabilize the connection to the mRNA. <scene name='86/868187/Zz/3'>The domain</scene> includes :<br />
***A <scene name='86/868187/Rd_turn/1'>Rubredoxin turn</scene> (Rd turn, residues 515-520), which is stabilized by hydrogen bonds between amide and sulfure.<br />
***β-hairpin with <scene name='86/868187/B1/1'>β1</scene> (residues 525-527) and <scene name='86/868187/B2/1'>β2</scene> (residues 533-535) between which there is an helical turn stabilized by hydrogen bonds.<br />
***An <scene name='86/868187/A/1'>α1 helix</scene> (residues 538-545) which forms the second bridge between the two zinc-binding sites. The surface-exposed face of the helix has a potential for specific intermolecular interactions with nucleic acids or proteins.<br />
***A 3<sub>10</sub> <scene name='86/868187/310/1'> helical turn</scene> (residues 550-552).<br />
***2 zinc binding sites, the first one is composed of <scene name='86/868187/Z1/3'>Cys515, Cys518, Cys537, Cys540</scene> and the second is composed of <scene name='86/868187/Z2/2'>Cys527, Cys532, His545 and His553</scene>.<br />
** '''RRMs patterns''' <ref>DOI 10.1101/gad.241133.114</ref><br />
==Your Heading Here (maybe something like 'Structure')==<br />
<StructureSection load='2MKK' size='350' side='right' caption='RNA binding to RRM' scene=''><br />
</StructureSection><br />
<br />
== Function ==<br />
CPEB protein regulates the length of the polyA tail which allows to control the translation. It binds to mRNA and in association with some factors, can act as a translational repressor or activator, depending on the factors. <br />
<br />
A specific arrangement of CPEs in mRNA can lead to the repression of the translation. In this case, the CPEB can form a dimer which could avoid the bound of the polyA polymerase complex in 2 different ways. It could prevent the association of ePAB with the polyA tail because CPEB recruits the deadenylase PARN which reduce the length of the polyA tail. It could disrupt the interaction between the binding factors of the translation [https://en.wikipedia.org/wiki/EIF4E eIF4E] and [https://en.wikipedia.org/wiki/EIF4G eIF4G] too, because CPEB recruits the protein Maskin which blocks eIF4G recruitment too. This prevents the bound of the cap machinery to the mRNA and therefore inhibits the translation.<br />
<br />
On the other hand, the CPEB can activate the translation. Indeed, in the cytoplasm, there are some repressed or silenced mRNA with a short polyA tail. They can be activated by cytoplasmic polyadenylation thanks to a hormonal stimulation. This stimulation can lead to the phosphorylation of CPEB which increase its affinity with the [https://en.m.wikipedia.org/wiki/Cleavage_and_polyadenylation_specificity_factor CPSF] (Cleavage and Polyadenylation Specificity Factor) and decrease the binding between CPEB and PARN. CPSF binds to the mRNA at the sequence 3’ of the tail of the mRNA (AAUAAA) and recruits the poly(A) polymerase which leads to the elongation of the polyA tail and therefore to the activation of the translation. <br />
<br />
<br />
== Disease ==<br />
<br />
<br />
== References ==<br />
<references/></div>Rose Buhlmannhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1654&diff=3341194Sandbox Reserved 16542021-01-09T18:26:18Z<p>Rose Buhlmann: </p>
<hr />
<div>{{Sandbox_Reserved_ESBS20_}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Cytoplasmic Polyadenylation Element-Binding Protein (CPEB)==<br />
[https://en.wikipedia.org/wiki/CPEB CPEB ](Cytoplasmic polyadenylation element binding protein) is present in most vertebrates and invertebrates and can activate or inhibit translation. In human body, there are 4 different isoforms of CPEB (CPEB1, CPEB2, CPEB3, CPEB4), which interact differently with mRNA. <br />
<br />
== Structure ==<br />
All CPEB proteins have a similar structure :<br />
* A N-terminal region which is a regulatory region with phosphorylation and dephosphorylation sites. This region is variable in length and composition.<br />
* A C-terminal region, composed of 2 recognition patterns : RRMs domains and zinc finger domains.<br />
** '''Zinc finger patterns''' <ref>DOI 10.1016/j.jmb.2013.03.009</ref><br />
<StructureSection load='2m13' size='340' side='left' caption='Caption for this structure' scene=''><br />
</StructureSection><br />
About 54 residues with 6 cysteines and 2 histidines involved in a bond with a zinc atom, conserved for all isoforms and species. The modification of one of the eight zinc ligands destabilize the connection to the mRNA. <scene name='86/868187/Zz/3'>The domain</scene> includes :<br />
***A <scene name='86/868187/Rd_turn/1'>Rubredoxin turn</scene> (Rd turn, residues 515-520), which is stabilized by hydrogen bonds between amide and sulfure.<br />
***β-hairpin with <scene name='86/868187/B1/1'>β1</scene> (residues 525-527) and <scene name='86/868187/B2/1'>β2</scene> (residues 533-535) between which there is an helical turn stabilized by hydrogen bonds.<br />
***An <scene name='86/868187/A/1'>α1 helix</scene> (residues 538-545) which forms the second bridge between the two zinc-binding sites. The surface-exposed face of the helix has a potential for specific intermolecular interactions with nucleic acids or proteins.<br />
***A 3<sub>10</sub> <scene name='86/868187/310/1'> helical turn</scene> (residues 550-552).<br />
***2 zinc binding sites, the first one is composed of <scene name='86/868187/Z1/3'>Cys515, Cys518, Cys537, Cys540</scene> and the second is composed of <scene name='86/868187/Z2/2'>Cys527, Cys532, His545 and His553</scene>.<br />
** '''RRMs patterns''' <ref>DOI 10.1101/gad.241133.114</ref><br />
==Your Heading Here (maybe something like 'Structure')==<br />
<StructureSection load='2MKK' size='350' side='right' caption='RNA binding to RRM' scene=''><br />
</StructureSection><br />
<br />
== Function ==<br />
CPEB protein regulates the length of the polyA tail which allows to control the translation. It binds to mRNA and in association with some factors, can act as a translational repressor or activator, depending on the factors. <br />
<br />
A specific arrangement of CPEs in mRNA can lead to the repression of the translation. In this case, the CPEB can form a dimer which could avoid the bound of the polyA polymerase complex in 2 different ways. It could prevent the association of ePAB with the polyA tail because CPEB recruits the deadenylase PARN which reduce the length of the polyA tail. It could disrupt the interaction between the binding factors of the translation [https://en.wikipedia.org/wiki/EIF4E eIF4E] and [https://en.wikipedia.org/wiki/EIF4G eIF4G] too, because CPEB recruits the protein Maskin which blocks eIF4G recruitment too. This prevents the bound of the cap machinery to the mRNA and therefore inhibits the translation.<br />
<br />
On the other hand, the CPEB can activate the translation. Indeed, in the cytoplasm, there are some repressed or silenced mRNA with a short polyA tail. They can be activated by cytoplasmic polyadenylation thanks to a hormonal stimulation. This stimulation can lead to the phosphorylation of CPEB which increase its affinity with the CPSF (Cleavage and Polyadenylation Specificity Factor) and decrease the binding between CPEB and PARN. CPSF binds to the mRNA at the sequence 3’ of the tail of the mRNA (AAUAAA) and recruits the poly(A) polymerase which leads to the elongation of the polyA tail and therefore to the activation of the translation. <br />
<br />
<br />
== Disease ==<br />
<br />
<br />
== References ==<br />
<references/></div>Rose Buhlmannhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1654&diff=3341193Sandbox Reserved 16542021-01-09T18:20:00Z<p>Rose Buhlmann: </p>
<hr />
<div>{{Sandbox_Reserved_ESBS20_}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Cytoplasmic Polyadenylation Element-Binding Protein (CPEB)==<br />
[https://en.wikipedia.org/wiki/CPEB CPEB ](Cytoplasmic polyadenylation element binding protein) is present in most vertebrates and invertebrates and can activate or inhibit translation. In human body, there are 4 different isoforms of CPEB (CPEB1, CPEB2, CPEB3, CPEB4), which interact differently with mRNA. <br />
<br />
== Structure ==<br />
All CPEB proteins have a similar structure :<br />
* A N-terminal region which is a regulatory region with phosphorylation and dephosphorylation sites. This region is variable in length and composition.<br />
* A C-terminal region, composed of 2 recognition patterns : RRMs domains and zinc finger domains.<br />
** '''Zinc finger patterns''' <ref>DOI 10.1016/j.jmb.2013.03.009</ref><br />
<StructureSection load='2m13' size='340' side='left' caption='Caption for this structure' scene=''><br />
</StructureSection><br />
About 54 residues with 6 cysteines and 2 histidines involved in a bond with a zinc atom, conserved for all isoforms and species. The modification of one of the eight zinc ligands destabilize the connection to the mRNA. <scene name='86/868187/Zz/3'>The domain</scene> includes :<br />
***A <scene name='86/868187/Rd_turn/1'>Rubredoxin turn</scene> (Rd turn, residues 515-520), which is stabilized by hydrogen bonds between amide and sulfure.<br />
***β-hairpin with <scene name='86/868187/B1/1'>β1</scene> (residues 525-527) and <scene name='86/868187/B2/1'>β2</scene> (residues 533-535) between which there is an helical turn stabilized by hydrogen bonds.<br />
***An <scene name='86/868187/A/1'>α1 helix</scene> (residues 538-545) which forms the second bridge between the two zinc-binding sites. The surface-exposed face of the helix has a potential for specific intermolecular interactions with nucleic acids or proteins.<br />
***A 3<sub>10</sub> <scene name='86/868187/310/1'> helical turn</scene> (residues 550-552).<br />
***2 zinc binding sites, the first one is composed of <scene name='86/868187/Z1/3'>Cys515, Cys518, Cys537, Cys540</scene> and the second is composed of <scene name='86/868187/Z2/2'>Cys527, Cys532, His545 and His553</scene>.<br />
** '''RRMs patterns''' <ref>DOI 10.1101/gad.241133.114</ref><br />
==Your Heading Here (maybe something like 'Structure')==<br />
<StructureSection load='2MKK' size='350' side='right' caption='RNA binding to RRM' scene=''><br />
</StructureSection><br />
<br />
== Function ==<br />
CPEB protein regulates the length of the polyA tail which allows to control the translation. It binds to mRNA and in association with some factors, can act as a translational repressor or activator, depending on the factors. <br />
<br />
A specific arrangement of CPEs in mRNA can lead to the repression of the translation. In this case, the CPEB can form a dimer which could avoid the bound of the polyA polymerase complex in 2 different ways. It could prevent the association of ePAB with the polyA tail because CPEB recruits the deadenylase PARN which reduce the length of the polyA tail. It could disrupt the interaction between the binding factors of the translation eIF4E and [https://en.wikipedia.org/wiki/EIF4G eIF4G] too, because CPEB recruits the protein Maskin which blocks eIF4G recruitment too. This prevents the bound of the cap machinery to the mRNA and therefore inhibits the translation.<br />
<br />
On the other hand, the CPEB can activate the translation. Indeed, in the cytoplasm, there are some repressed or silenced mRNA with a short polyA tail. They can be activated by cytoplasmic polyadenylation thanks to a hormonal stimulation. This stimulation can lead to the phosphorylation of CPEB which increase its affinity with the CPSF (Cleavage and Polyadenylation Specificity Factor) and decrease the binding between CPEB and PARN. CPSF binds to the mRNA at the sequence 3’ of the tail of the mRNA (AAUAAA) and recruits the poly(A) polymerase which leads to the elongation of the polyA tail and therefore to the activation of the translation. <br />
<br />
<br />
== Disease ==<br />
<br />
<br />
== References ==<br />
<references/></div>Rose Buhlmannhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1654&diff=3341192Sandbox Reserved 16542021-01-09T18:16:49Z<p>Rose Buhlmann: </p>
<hr />
<div>{{Sandbox_Reserved_ESBS20_}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Cytoplasmic Polyadenylation Element-Binding Protein (CPEB)==<br />
[https://en.wikipedia.org/wiki/CPEB CPEB ](Cytoplasmic polyadenylation element binding protein) is present in most vertebrates and invertebrates and can activate or inhibit translation. In human body, there are 4 different isoforms of CPEB (CPEB1, CPEB2, CPEB3, CPEB4), which interact differently with mRNA. <br />
<br />
== Structure ==<br />
All CPEB proteins have a similar structure :<br />
* A N-terminal region which is a regulatory region with phosphorylation and dephosphorylation sites. This region is variable in length and composition.<br />
* A C-terminal region, composed of 2 recognition patterns : RRMs domains and zinc finger domains.<br />
** '''Zinc finger patterns''' <ref>DOI 10.1016/j.jmb.2013.03.009</ref><br />
<StructureSection load='2m13' size='340' side='left' caption='Caption for this structure' scene=''><br />
</StructureSection><br />
About 54 residues with 6 cysteines and 2 histidines involved in a bond with a zinc atom, conserved for all isoforms and species. The modification of one of the eight zinc ligands destabilize the connection to the mRNA. <scene name='86/868187/Zz/3'>The domain</scene> includes :<br />
***A <scene name='86/868187/Rd_turn/1'>Rubredoxin turn</scene> (Rd turn, residues 515-520), which is stabilized by hydrogen bonds between amide and sulfure.<br />
***β-hairpin with <scene name='86/868187/B1/1'>β1</scene> (residues 525-527) and <scene name='86/868187/B2/1'>β2</scene> (residues 533-535) between which there is an helical turn stabilized by hydrogen bonds.<br />
***An <scene name='86/868187/A/1'>α1 helix</scene> (residues 538-545) which forms the second bridge between the two zinc-binding sites. The surface-exposed face of the helix has a potential for specific intermolecular interactions with nucleic acids or proteins.<br />
***A 3<sub>10</sub> <scene name='86/868187/310/1'> helical turn</scene> (residues 550-552).<br />
***2 zinc binding sites, the first one is composed of <scene name='86/868187/Z1/3'>Cys515, Cys518, Cys537, Cys540</scene> and the second is composed of <scene name='86/868187/Z2/2'>Cys527, Cys532, His545 and His553</scene>.<br />
** '''RRMs patterns''' <ref>DOI 10.1101/gad.241133.114</ref><br />
==Your Heading Here (maybe something like 'Structure')==<br />
<StructureSection load='2MKK' size='350' side='right' caption='RNA binding to RRM' scene=''><br />
</StructureSection><br />
<br />
== Function ==<br />
CPEB protein regulates the length of the polyA tail which allows to control the translation. It binds to mRNA and in association with some factors, can act as a translational repressor or activator, depending on the factors. <br />
<br />
A specific arrangement of CPEs in mRNA can lead to the repression of the translation. In this case, the CPEB can form a dimer which could avoid the bound of the polyA polymerase complex in 2 different ways. It could prevent the association of ePAB with the polyA tail because CPEB recruits the deadenylase PARN which reduce the length of the polyA tail. It could disrupt the interaction between the binding factors of the translation eIF4E and eIF4G too, because CPEB recruits the protein Maskin which blocks eIF4G recruitment too. This prevents the bound of the cap machinery to the mRNA and therefore inhibits the translation.<br />
<br />
On the other hand, the CPEB can activate the translation. Indeed, in the cytoplasm, there are some repressed or silenced mRNA with a short polyA tail. They can be activated by cytoplasmic polyadenylation thanks to a hormonal stimulation. This stimulation can lead to the phosphorylation of CPEB which increase its affinity with the CPSF (Cleavage and Polyadenylation Specificity Factor) and decrease the binding between CPEB and PARN. CPSF binds to the mRNA at the sequence 3’ of the tail of the mRNA (AAUAAA) and recruits the poly(A) polymerase which leads to the elongation of the polyA tail and therefore to the activation of the translation. <br />
<br />
<br />
== Disease ==<br />
<br />
<br />
== References ==<br />
<references/></div>Rose Buhlmannhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1654&diff=3341190Sandbox Reserved 16542021-01-09T18:11:56Z<p>Rose Buhlmann: </p>
<hr />
<div>{{Sandbox_Reserved_ESBS20_}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Cytoplasmic Polyadenylation Element-Binding Protein (CPEB)==<br />
CPEB (Cytoplasmic polyadenylation element binding protein) is present in most vertebrates and invertebrates and can activate or inhibit translation. In human body, there are 4 different isoforms of CPEB (CPEB1, CPEB2, CPEB3, CPEB4), which interact differently with mRNA. <br />
<br />
== Structure ==<br />
All CPEB proteins have a similar structure :<br />
* A N-terminal region which is a regulatory region with phosphorylation and dephosphorylation sites. This region is variable in length and composition.<br />
* A C-terminal region, composed of 2 recognition patterns : RRMs domains and zinc finger domains.<br />
** '''Zinc finger patterns''' <ref>DOI 10.1016/j.jmb.2013.03.009</ref><br />
<StructureSection load='2m13' size='340' side='left' caption='Caption for this structure' scene=''><br />
</StructureSection><br />
About 54 residues with 6 cysteines and 2 histidines involved in a bond with a zinc atom, conserved for all isoforms and species. The modification of one of the eight zinc ligands destabilize the connection to the mRNA. <scene name='86/868187/Zz/3'>The domain</scene> includes :<br />
***A <scene name='86/868187/Rd_turn/1'>Rubredoxin turn</scene> (Rd turn, residues 515-520), which is stabilized by hydrogen bonds between amide and sulfure.<br />
***β-hairpin with <scene name='86/868187/B1/1'>β1</scene> (residues 525-527) and <scene name='86/868187/B2/1'>β2</scene> (residues 533-535) between which there is an helical turn stabilized by hydrogen bonds.<br />
***An <scene name='86/868187/A/1'>α1 helix</scene> (residues 538-545) which forms the second bridge between the two zinc-binding sites. The surface-exposed face of the helix has a potential for specific intermolecular interactions with nucleic acids or proteins.<br />
***A 3<sub>10</sub> <scene name='86/868187/310/1'> helical turn</scene> (residues 550-552).<br />
***2 zinc binding sites, the first one is composed of <scene name='86/868187/Z1/3'>Cys515, Cys518, Cys537, Cys540</scene> and the second is composed of <scene name='86/868187/Z2/2'>Cys527, Cys532, His545 and His553</scene>.<br />
** '''RRMs patterns''' <ref>DOI 10.1101/gad.241133.114</ref><br />
<Structure load='2MKK' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
<br />
== Function ==<br />
CPEB protein regulates the length of the polyA tail which allows to control the translation. It binds to mRNA and in association with some factors, can act as a translational repressor or activator, depending on the factors. <br />
<br />
A specific arrangement of CPEs in mRNA can lead to the repression of the translation. In this case, the CPEB can form a dimer which could avoid the bound of the polyA polymerase complex in 2 different ways. It could prevent the association of ePAB with the polyA tail because CPEB recruits the deadenylase PARN which reduce the length of the polyA tail. It could disrupt the interaction between the binding factors of the translation eIF4E and eIF4G too, because CPEB recruits the protein Maskin which blocks eIF4G recruitment too. This prevents the bound of the cap machinery to the mRNA and therefore inhibits the translation.<br />
<br />
On the other hand, the CPEB can activate the translation. Indeed, in the cytoplasm, there are some repressed or silenced mRNA with a short polyA tail. They can be activated by cytoplasmic polyadenylation thanks to a hormonal stimulation. This stimulation can lead to the phosphorylation of CPEB which increase its affinity with the CPSF (Cleavage and Polyadenylation Specificity Factor) and decrease the binding between CPEB and PARN. CPSF binds to the mRNA at the sequence 3’ of the tail of the mRNA (AAUAAA) and recruits the poly(A) polymerase which leads to the elongation of the polyA tail and therefore to the activation of the translation. <br />
<br />
<br />
== Disease ==<br />
<br />
<br />
== References ==<br />
<references/></div>Rose Buhlmann