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 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. [1]
Several other fibrillin proteins exist such as Fibrillin 2 [2], that plays a role in early elastogenesis. Fibrillin 3 is thought to be located mainly in the brain [3] and Fibrillin 4 has a sequence similar to Fibrillin 2. [4]
Structure
3D model represents these parts of fibrillin-1: , and .
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 . 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 (CYS1-CYS3, CYS2-CYS4, CYS5-CYS6) stabilizing the secondary structure of the protein. Cb-EGF units contain also a 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. [5]
FBN1 gene
This gene [6] 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]
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, versican and LTBP-1. Those microfibrils constitute the elastic and non-elastic human connective tissues such as the dermis or the organs.
Role in the cytokine and growth factor regulation:
This protein plays an important role in the 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. [7] [8]
Fetal cardiovascular development:
The FBN-1 gene is involved in a variety of embryonic developmental programs. The microfibrils that are made from fibrillin-1 contribute to both elastic and non-elastic structures. The formation of the elastic fibers in the heart valves and the aorta require the involvement of both FBN-1 and FBN-2.It has been shown that both FBN-1 and FBN-2, along with the other components of elastic fibers, are expressed in the embryonic semilunar valves as early as 4 weeks of gestation. These molecules interact to form the elastic fibers in the ventricularis layer of the semilunar valves. Fibrillin-1 and fibrillin-2 are also crucial for the development of elastic fibers in the aorta. While expression of fibrillin-2 decreases significantly after fetal development, the expression of fibrillin-1 continues into adulthood. This supports the idea that fibrillin-2 dictates the development of early elastic fibers, while fibrillin-1 provides the structural support of mature elastic fibers.[9]
Diseases caused by mutation
Dominant mutations in the fibrillin-1 gene cause Marfan syndrome (MFS) and illustrate the physiological functions of elastic fibers. Most of the thousand known fibrillin-1 mutations make the protein unstable and susceptible to proteolysis. Other point mutations interfere with folding. All patients are heterozygotes.
Elastic fibers of patients with Marfan syndrome are poorly formed, accounting for most of the pathological changes. Most dangerously, weakness of elastic fibers in the aorta leads to an enlargement of the vessel, called an aneurysm, which is prone to rupture, with fatal consequences. Prophylactic replacement of the aorta with a synthetic graft and medical treatment with drugs that block adrenergic receptors allow patients a nearly normal life span. In some patients, a floppy mitral valve in the heart causes reflux of blood from the left ventricle back into the left atrium. Weak elastic fibers that suspend the lens of the eye result in dislocation of the lens and impaired vision. Weak elastic fibers result in lax joints and curvature of the spine. Most affected patients are tall, with long limbs and fingers, but the connection of these features to fibrillin is not known.
[10]
It exists nearly 1 000 different mutations possible in 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 Fibrillin-1 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 . 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-bp in the blood because the factors cannot bind to the protein due to a change in the binding domain's structure. [11]
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 cysteine localization for the protein structure. Also, a mutation of the TGFBR2 gene coding for the TGF-bp has been found and can cause the "Type 2 Marfan syndrome". However, not much has been discovered on the subject yet. [12] [13]
