Sandbox Reserved 1654: Difference between revisions

From Proteopedia
Jump to navigationJump to search
← Older edit
No edit summary
No edit summary
 
(54 intermediate revisions by 4 users not shown)
Line 1: Line 1:
{{Sandbox_Reserved_ESBS20_}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE -->
{{Sandbox_Reserved_ESBS20_}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE -->
==Cytoplasmic Polyadenylation Element-Binding Protein (CPEB)==
==''' Cytoplasmic Polyadenylation Element-Binding Protein (CPEB) ''' ==
[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.  
[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], which has a length of 65 amino acids, 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>.
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.


== Structure ==
== ''' Structure ''' ==
All CPEB proteins have a similar structure :
All CPEB proteins have a similar structure :
* A N-terminal region which is a regulatory region with phosphorylation and dephosphorylation sites. This region is variable in length and composition.
* A N-terminal region which is a regulatory region with phosphorylation and dephosphorylation sites. This region is variable in length and composition.
* A C-terminal region, composed of 2 recognition patterns : RRMs domains and zinc finger domains.
* A C-terminal region, composed of 2 recognition patterns : RRMs domains and zinc finger domains.
** '''Zinc finger patterns''' <ref>DOI 10.1016/j.jmb.2013.03.009</ref>
** '''Zinc finger patterns'''<ref>DOI 10.1016/j.jmb.2013.03.009</ref> [https://www.rcsb.org/structure/2M13]
<StructureSection load='2m13' size='340' side='left' caption='Caption for this structure' scene=''>
 
<table><tr><td colspan='3'><br>
</td></tr><tr id='Total Structure Weight'><td class="sblockLbl"><b>Total Structure Weight</b></td><td class="sblockDat"><span class='plainlinks'><scene name='86/868190/5czx_heavy_chain_labeled/1'>7,9kDa</scene></span></td></tr><tr id='Atom Count'><td class="sblockLbl"><b>Atom Count</b></td><td class="sblockDat"><span class='plainlinks'>543</span></td></tr><tr id='Number of protein chains'><td class="sblockLbl"><b>Number of protein chains</b></td><td class="sblockDat">1</td></tr>
 
<StructureSection load='2m13' size='340' side='left' caption='Zinc finger domain' scene=''>
</StructureSection>
</StructureSection>
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 :
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 :
***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.
***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.
***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.
***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.
***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.
***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. 
***A 3<sub>10</sub> <scene name='86/868187/310/1'> helical turn</scene> (residues 550-552).
***A 3<sub>10</sub> <scene name='86/868187/310/1'> helical turn</scene> (residues 550-552).
***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>.
***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>.
** '''RRMs patterns''' <ref>DOI 10.1101/gad.241133.114</ref>
** '''RRMs patterns'''<ref>DOI 10.1101/gad.241133.114</ref> [https://www.rcsb.org/structure/2MKK]
==Your Heading Here (maybe something like 'Structure')==
<table><tr><td colspan='3'><br>
<StructureSection load='2MKK' size='350' side='right' caption='RNA binding to RRM' scene=''>
</td></tr><tr id='Total Structure Weight'><td class="sblockLbl"><b>Total Structure Weight</b></td><td class="sblockDat"><span class='plainlinks'><scene name='86/868190/5czx_heavy_chain_labeled/1'>25,44kDa</scene></span></td></tr><tr id='Atom Count'><td class="sblockLbl"><b>Atom Count</b></td><td class="sblockDat"><span class='plainlinks'>1786</span></td></tr><tr id='Number of protein chains'><td class="sblockLbl"><b>Number of protein chains</b></td><td class="sblockDat">1</td></tr>  id='Number of nucleic acid chains'><td class="sblockLbl"><b>Number of nucleic acid chains</b></td><td class="sblockDat">1</td></tr>
 
 
<StructureSection load='2MKK' size='350' side='right' caption='RNA binding to RRMs' scene=''>
</StructureSection>
</StructureSection>
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:
***<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>.
***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>.
***<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.
***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.
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.
== ''' Function ''' ==
===  ''' General function ''' ===
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" />.
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.
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.
[[Image: CPEB-mediated translational control.jpg#filehistory| thumb |left|360px| upright=10/'''CPEB-mediated translational control''']]


== Function ==
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.
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.  


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.
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" />.  


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.
===  ''' Function in memory ''' ===


Long-term and short-term memories differ by the duration of their retention. Long-term memory formation needs transcription and translation of stored mRNAs. CPEB operate in the post synaptic domain of neurons. CPEB is stimulated by a neuronal stimulation, it “activates translation of CaMKII and similar mRNAs. It also associates with motor proteins for mRNA transport and has a role in packaging of bound mRNAs to RNP complexes. CPEB initiates polyadenylation induced translation of dormant mRNAs during Xenopus oocyte maturation. In developing oocytes, following nuclear export, CPE containing mRNAs are bound by CPEB1 as well as other interacting proteins like PARN (poly A ribonuclease) and Gld2 (polyA polymerase), leading to removal of polyA tail of mRNAs, as PARN overrides Gld2 activity. This leads to translational suppression of mRNAs. However upon activity-induced phosphorylation of CPEB, PARN dissociates from the complex and the mRNA is polyadenylated leading to translation.”
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5449092/]
== ''' Diseases ''' ==
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" />.


== Disease ==
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>.




== References ==
== ''' References ''' ==
<references/>
<references/>
Retrieved from "https://proteopedia.org/Sandbox_Reserved_1654"