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{{Sandbox_Reserved_ESBS20_}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --> | {{Sandbox_Reserved_ESBS20_}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --> | ||
==Fibrillin-1== | ==Fibrillin-1== | ||
<StructureSection load='2W86' size='340' side='right' caption='3D structure of fibrillin-1 (PDB ID : 2W86)' scene='86/868178/Protein/1'> | <StructureSection load='2W86' size='340' side='right' caption='3D structure of fibrillin-1 (PDB ID : 2W86)' scene='86/868178/Protein/1'> | ||
'''Fibrillin-1''' is a protein that is encoded in human bodies by the gene FBN1 situated on chromosome 15. Fibrillin-1 is a single protein chain of 230kb involving 65 exons from the class of '''[https://en.wikipedia.org/wiki/Glycoprotein glycoproteins]''' with a mass of 350kDa. The protein forms microfibrils located in the extracellular matrix, and thus has a role in the structural support of cells in elastic and nonelastic connective tissues in the human body. <ref>Handford, P. A. (2000). Fibrillin-1, a calcium binding protein of extracellular matrix. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1498(2), 84–90. https://doi.org/10.1016/S0167-4889(00)00085-9</ref> | '''Fibrillin-1''' is a protein that is encoded in human bodies by the gene FBN1 situated on chromosome 15. Fibrillin-1 is a single protein chain of 230kb involving 65 exons from the class of '''[https://en.wikipedia.org/wiki/Glycoprotein glycoproteins]''' with a mass of 350kDa. The protein forms microfibrils located in the extracellular matrix, and thus has a role in the structural support of cells in elastic and nonelastic connective tissues in the human body. <ref>Handford, P. A. (2000). Fibrillin-1, a calcium binding protein of extracellular matrix. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1498(2), 84–90. https://doi.org/10.1016/S0167-4889(00)00085-9</ref> | ||
Several other fibrillin protein exist such as Fibrillin 2, that plays a role in early elastogenesis. Fibrillin 3 is thought to be located mainly in the brain. And Fibrillin 4 that have a sequence similar to Fibrillin 2 | Several other fibrillin protein exist such as Fibrillin 2, that plays a role in early elastogenesis. Fibrillin 3 is thought to be located mainly in the brain. And Fibrillin 4 that have a sequence similar to Fibrillin 2 | ||
== Structure == | == Structure == | ||
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The protein fibrillin-1 contains 59 subunits either called '''epidermal growth factor-like domain''' ([[EGF]]), or '''transforming growth factor β binding protein-like domain''' (8 TGF-bp). EGFs are repeated in tandem along with the whole protein which represents about 75% of the total Fibrillin-1 length, and they are interrupted by the insertion of the TGF-bp units, which contain 8 cysteines each which form <scene name='86/868178/Disulfide_bridges_in_tgf-bp/2'>4 disulfide bridges</scene>. In total, there are 47 motifs of EGF in one Fibrillin-1, but only 43 of them contain calcium-binding sequences. In consequence, these EGF are named cb-EGF for their ability to bind calcium cations. Each EGF or cb-EGF unit contains 6 residues of cysteine which form <scene name='86/868178/Disulfide_bridges/1'>3 disulfide bridges</scene> (CYS1-CYS3, CYS2-CYS4, CYS5-CYS6) stabilizing the secondary structure of the protein. Cb-EGF units contain also a <scene name='86/868178/Ca_binding_site/1'>Ca2+ binding site</scene> composed especially of amino acids that contain an oxygen atom, or groups with an azote in their lateral chains (aspartic and glutamic acids, serine, asparagine and glutamine). These amino acids stabilize the calcium cation by interactions between positively charged cation and hetero-atoms (oxygen or azote) of the amino acid's lateral chain. Consequently, a pentagonal bipyramidal binding site is created in which one calcium cation is bound in every cb-EGF subunit of the fibrillin-1 protein. <ref>Sandra Schrenk Carola Cenzi Thomas Bertalot Maria Teresa Conconi Rosa Di Liddo, (2017), pages: 1213-1223,https://doi.org/10.3892/ijmm.2017.3343</ref> | The protein fibrillin-1 contains 59 subunits either called '''epidermal growth factor-like domain''' ([[EGF]]), or '''transforming growth factor β binding protein-like domain''' (8 TGF-bp). EGFs are repeated in tandem along with the whole protein which represents about 75% of the total Fibrillin-1 length, and they are interrupted by the insertion of the TGF-bp units, which contain 8 cysteines each which form <scene name='86/868178/Disulfide_bridges_in_tgf-bp/2'>4 disulfide bridges</scene>. In total, there are 47 motifs of EGF in one Fibrillin-1, but only 43 of them contain calcium-binding sequences. In consequence, these EGF are named cb-EGF for their ability to bind calcium cations. Each EGF or cb-EGF unit contains 6 residues of cysteine which form <scene name='86/868178/Disulfide_bridges/1'>3 disulfide bridges</scene> (CYS1-CYS3, CYS2-CYS4, CYS5-CYS6) stabilizing the secondary structure of the protein. Cb-EGF units contain also a <scene name='86/868178/Ca_binding_site/1'>Ca2+ binding site</scene> composed especially of amino acids that contain an oxygen atom, or groups with an azote in their lateral chains (aspartic and glutamic acids, serine, asparagine and glutamine). These amino acids stabilize the calcium cation by interactions between positively charged cation and hetero-atoms (oxygen or azote) of the amino acid's lateral chain. Consequently, a pentagonal bipyramidal binding site is created in which one calcium cation is bound in every cb-EGF subunit of the fibrillin-1 protein. <ref>Sandra Schrenk Carola Cenzi Thomas Bertalot Maria Teresa Conconi Rosa Di Liddo, (2017), pages: 1213-1223,https://doi.org/10.3892/ijmm.2017.3343</ref> | ||
== Biological Function == | == Biological Function == | ||
Fibrillin-1 is a ubiquitous protein mostly expressed in muscles in its monomeric form. The monomers then polymerize to form the 10 to 12nm of diameter '''microfibrils'''. In the microfibrils the fibrillin-1 is associated to various proteins such as MAGP-1, MAGP-2, fibulin 2 and fibulin 5, elastin, versicane and LTBP-1. Those microfibrils constitute the elastic and non-elastic human connective tissues such as the dermis or the organs. This protein plays an important role in the [https://en.wikipedia.org/wiki/Cytokine cytokine] and growth factor regulation. For example, fibrillin-1 can modulate the bioavailability of TGFβ1, which is a cytokine that regulates cell survival. Changed TGFβ signaling is a significant factor in the development of certain diseases. A fibrillin-1 segment encoded by exons 44-49 triggers the release of TGFβ1 and consequently stimulates TGFβ receptor-mediated Smad2 signaling. Thereby, specific gene activation or repression can be induced. <ref>Robert N. Ono, Gerhard Sengle, Noe L. Charbonneau, Valerie Carlberg, Hans Peter Bächinger, Takako Sasaki, Sui Lee-Arteaga, Lior Zilberberg, Daniel B. Rifkin, Francesco Ramirez, Mon-LiChu, Lynn Y.Sakai. (2009). Latent Transforming Growth Factor β-binding Proteins and Fibulins Compete for Fibrillin-1 and Exhibit Exquisite Specificities in Binding Sites. ''Journal of Biological Chemistry'', volume (284). https://www.sciencedirect.com/science/article/pii/S0021925818665056</ref> <ref> Shazia S. Chaudhry, Stuart A. Cain, Amanda Morgan, Sarah L. Dallas, C. Adrian Shuttleworth, Cay M. Kielty; Fibrillin-1 regulates the bioavailability of TGFβ1. J Cell Biol 29 January 2007; 176 (3): 355–367. doi: https://doi.org/10.1083/jcb.200608167</ref> | Fibrillin-1 is a ubiquitous protein mostly expressed in muscles in its monomeric form. The monomers then polymerize to form the 10 to 12nm of diameter '''microfibrils'''. In the microfibrils the fibrillin-1 is associated to various proteins such as MAGP-1, MAGP-2, fibulin 2 and fibulin 5, elastin, versicane and LTBP-1. Those microfibrils constitute the elastic and non-elastic human connective tissues such as the dermis or the organs. This protein plays an important role in the [https://en.wikipedia.org/wiki/Cytokine cytokine] and growth factor regulation. For example, fibrillin-1 can modulate the bioavailability of TGFβ1, which is a cytokine that regulates cell survival. Changed TGFβ signaling is a significant factor in the development of certain diseases. A fibrillin-1 segment encoded by exons 44-49 triggers the release of TGFβ1 and consequently stimulates TGFβ receptor-mediated Smad2 signaling. Thereby, specific gene activation or repression can be induced. <ref>Robert N. Ono, Gerhard Sengle, Noe L. Charbonneau, Valerie Carlberg, Hans Peter Bächinger, Takako Sasaki, Sui Lee-Arteaga, Lior Zilberberg, Daniel B. Rifkin, Francesco Ramirez, Mon-LiChu, Lynn Y.Sakai. (2009). Latent Transforming Growth Factor β-binding Proteins and Fibulins Compete for Fibrillin-1 and Exhibit Exquisite Specificities in Binding Sites. ''Journal of Biological Chemistry'', volume (284). https://www.sciencedirect.com/science/article/pii/S0021925818665056</ref> <ref> Shazia S. Chaudhry, Stuart A. Cain, Amanda Morgan, Sarah L. Dallas, C. Adrian Shuttleworth, Cay M. Kielty; Fibrillin-1 regulates the bioavailability of TGFβ1. J Cell Biol 29 January 2007; 176 (3): 355–367. doi: https://doi.org/10.1083/jcb.200608167</ref> | ||
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== FBN1 gene == | |||
This gene encodes a member of the fibrillin family of proteins. The encoded preproprotein is proteolytically processed to generate two proteins including the extracellular matrix component fibrillin-1 and the protein hormone asprosin. Fibrillin-1 is an extracellular matrix glycoprotein that serves as a structural component of calcium-binding microfibrils. These microfibrils provide force-bearing structural support in elastic and nonelastic connective tissue throughout the body. Asprosin, secreted by white adipose tissue, has been shown to regulate glucose homeostasis. Mutations in this gene are associated with Marfan syndrome and the related MASS phenotype, as well as ectopia lentis syndrome, Weill-Marchesani syndrome, Shprintzen-Goldberg syndrome and neonatal progeroid syndrome. [provided by RefSeq, Apr 2016] | |||
== Diseases caused by mutation == | == Diseases caused by mutation == | ||
The [https://www.omim.org/entry/154700?search=marfan%20syndrome&highlight=%28syndrome%7Csyndromic%29%20marfan Marfan syndrome (MFS)] | The [https://www.omim.org/entry/154700?search=marfan%20syndrome&highlight=%28syndrome%7Csyndromic%29%20marfan Marfan syndrome (MFS)] | ||
