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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 from the class of glycoproteins with a mass of 350 kDa and it forms microfibrils located in the extracellular matrix. Thus, fibrillin-1 has a role in the structural support of cells in elastic and nonelastic connective tissue in the human body.

Structure

The protein contains multiple subunits called epidermal growth factor (EGF) and transforming growth factor β binding protein-like domain (7 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 stabilate 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 .

Disease

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 this mutation. The calcium cation cannot bind properly to the cb-EGF unit and therefore there is no stabilization of cb-EGF interdomain which causes defects in connective tissue.

Relevance

Structural highlights

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