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==Fibrillin - 1==
<StructureSection load='2W86' size='340' side='right' caption='3D structure of fibrillin-1 (PDB ID : 2W86)' scene=''>
'''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 '''glycoproteins''' class with a mass of 350 kDa. 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.

== Structure ==
The protein 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 lenght, and they are interrupted by the insertion of the TGF-bp unit. 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 (Proteopedia 3D visualization of two tandem cb-EGF). 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 by amino acids which contain an atom of oxygen or groups with azote in their lateral chains (D,N,S,Q,E). 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.

3D model represents these parts of fibrillin-1: <scene name='86/868178/Cbegf9/2'>cb-EGF9</scene>, second hybrid domain and <scene name='86/868178/Cbegf10/1'>cb-EGF10</scene>.

== 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 [[cytokine]] and growth factor regulation. <ref>Julien Wipff, Yannick Allanore, and Catherine Boileau. (2009). Interactions entre la Fibrilline-1 et le TGF-β. ''Médecine Sciences Paris'', volume (25). https://www.medecinesciences.org/en/articles/medsci/full_html/2009/02/medsci2009252p161/medsci2009252p161.html</ref>

== Disease caused by mutation ==
The [https://en.wikipedia.org/wiki/Marfan_syndrome Marfan syndrome (MFS)] is a genetic disorder due to a mutation of the FBN1 gene. Because Fibrillin1 is found in connective tissues, having this syndrome can cause severe damages to the ocular, skeletal and cardiovascular systems by affecting the organs’ tissues. Indeed, with fragile connective tissues due to badly synthesized microfibrils, the aorta can be deformed and disrupted which can induce internal bleeding, and lead to death. <ref>Marfan Syndrome.https://en.wikipedia.org/wiki/Marfan_syndrome Marfan syndrome</ref>

It exists nearly 1 000 different mutations on this gene but the most common one is a substitution of guanine by thymine at the 1538 nucleotide of the transcript. This type of mutation leads to a non-synonymous amino acid substitution '''Cys (cysteine) to Phe (phenylalanine)''' at the 528 position on the fibrillin1 gene. Because this cysteine is present in the calcium binding domain's polypeptide chain the epidermal growth factor-like domain's structure of FBN1 is modified by affecting the <scene name='86/868178/Disulfide_bridges/1'> disulfide bridge </scene> . The calcium cation cannot bind properly to the <scene name='86/868178/Ca_binding_site/1'> cb-EGF unit </scene> and therefore there is no stabilization of cb-EGF interdomain which causes defects in connective tissue. We can thus detect the Marfan syndrome by an increase of TGF β in the blood because the factors cannot bind to the protein due to a change in the binding domain's structure. <ref>E. Martínez-Quintana, F. Rodríguez-González, P. Garay-Sánchez, and A. Tugoresb. (2014).A Novel Fibrillin 1 Gene Mutation Leading to Marfan Syndrome with Minimal Cardiac Features. ''Molecular Syndormology'', volume (5), 236-240.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188161/</ref>

Other diseases can occur by the substitution of other cysteines of the FBN1 transcript such as C1, C2, C3, or C4. But the consequences of these mutations are much more severe. It shows the importance of the cysteines localization for the proteine's structure. Also, a mutation of the [https://en.wikipedia.org/wiki/TGF_beta_receptor_2 TGFBR2] gene coding for the TGF β has been found and can cause the "Type 2 Marfan syndrome". However, not much has been discovered on the subject yet. <ref>p.A. Handford. (2000).Fibrillin-1, a calcium-binding protein of extracellular matrix.''Biochimica et Biophysica Acta (BBA) - Molecular Cell Research'', volume (1498), 84-90.https://www.sciencedirect.com/science/article/pii/S0167488900000859</ref>

== Structural highlights ==

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.

</StructureSection>

== References ==

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