Fibrillin-1 (PDB ID: 2W86) is a protein which 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). EGF are repeated in tandem along the whole protein which represents about 75% of the total fibrillin-1 lenght, and they are interrupted by the insertion of 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 of EGF or cb-EGF unit contains 6 residues of cysteine which form (CYS1-CYS3,CYS2-CYS4,CYS5-CYS6)(Proteopedia 3D visualization of disulfide bridges) stabilizing the secondary structure of the protein. Cb-EGF units contain also a composed especially by aminoacids 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 positivly charged cation and hetero-atoms (oxygen or azote) of 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: , second hybrid domain and .
Microfibrils
The Fibrillin-1 is an ubiquitous protein mostly expressed in muscles though 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.
Disease caused by mutation
The Marfan syndrome (MFS) is a genetic disorder due to a mutation of the Fibrillin1 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 bad synthesized microfibrils, the aorta can be deformed which can provoke an internal bleeding, and lead to death.
It exists nearly a 1 000 of different mutations on this gene but the most common one is a substitution of a guanine by a 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 polypetide chain the epidermal growth factor-like domain's structure of FBN1 is modified by affecting the . The calcium cation cannot bind properly to the 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 proteine due to a change in the binding domain's structure.
Other diseases can occur by the substitution of other cysteines of the FBN1 transcript such as C1-C2, or C3-C4. But the consequences of these diseases are much more severe. It shows the importance of the cysteines localization for the proteine's structure. Also, a mutation of the TGFBR2 gene coding for the TGF β has been found and can cause the "Type 2 Marfan syndrome". But not much has been disovered on the subject yet.
Relevance
Structural highlights
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