Fibrillins There are two main sections in the

Fibrillinsare a family of high sulphide containing glycoproteins that help createelasticity within connective tissue, GC1 anytissue that supports organs by forming a framework that binds different tissuestogether. Connective tissues can also store fat and transport differentsubstances. It is made up of few cells but a large variety ofproteins that create the extracellular matrix.

Fibroblast cells secrete theextracellular matrix contents, which includes collagen, elastin and fibrillins.1 Fibrillins are made from amino acids joined together to form a peptide, whichGC2 interact with each other within the peptide chain to create a highly specific3D shape. If the configuration of the protein is changed, the functionality ofthe protein may be affected, and it is likely that the protein will not be ableto perform its role within the body.Fibrillinsform microfibrils 10-12 nm in length.2 There are two main sectionsin the fibrillin protein; 43 calcium-binding epidermal growth factor-likedomains (cbEGF) and 8 transforming growth factor B binding protein-likecysteine domains (TB).3,4 cbEGF domains are present in manydifferent proteins5, such as protein S, which works in theanticoagulant system6, and Notch-3, a receptor involved in geneexpression.

7Infibrillin-1, cbEGF domains have been shown to have antiparallel ? hairpin whichcontains three disulphide bridges. Calcium binds to cbEGF domains using ligandswhich arranges in a bipyramidal fashion. Six out of seven ligands areintradomain oxygen atoms, in the form of oxygen atoms on side groups or as partof a carbonyl. The seventh ligand has not yet been identified.8 TwocbEGF domains are involved in the stabilisation of the other cbEGF domains anddo not directly bind to calcium. cbEGF domains are organised into a rod shape;calcium has been shown to control the rigidity of the rod shape.

3,4,9TheTB domain comprises six antiparallel ? strands and 2 ? helices. It containsfour disulphide bridges which stabilise the structure. Six of the TB domainsare covalently bonded to cbEGF domains and has been shown to increase cbEGFdomain affinity to calcium atoms. TB domains bind to transforming growth factorbeta (TGF-?) proteins to store them within the matrix.6 Fibrillin-1 alsocontains a region that is high in proline and is thought to act as a hingeregion.3 Fibrillin-1is secreted from fibroblasts3 and has multiple functions within theextracellular matrix. The microfibrils that are formed from fibrillin-1 formelastic fibres which also incorporate lysyl-oxidase, proteoglycans and elastin.Fibrillin-1 is also present in tissues that do not contain elastin.

Best services for writing your paper according to Trustpilot

Premium Partner
From $18.00 per page
4,8 / 5
4,80
Writers Experience
4,80
Delivery
4,90
Support
4,70
Price
Recommended Service
From $13.90 per page
4,6 / 5
4,70
Writers Experience
4,70
Delivery
4,60
Support
4,60
Price
From $20.00 per page
4,5 / 5
4,80
Writers Experience
4,50
Delivery
4,40
Support
4,10
Price
* All Partners were chosen among 50+ writing services by our Customer Satisfaction Team

The fullextent of fibrillin-1 protein functions and the processes involved within theextracellular matrix has not yet been identified. Nonetheless,GC3 some roles of fibrillin-1 are known. Fibrillin-1 provides a framework todeposit tropoelastin, which is an important protein that allows elastic fibresto stretch and recoil.10 The ? hairpin within cbEGF domains havebeen shown to be a key component within this process. Additionally, fibrillin-1microfibrils are shown to be elastic, which can indicate their use in tissues,where elastin is not present, as an elastic fibre. The control of the rod shapein fibrillin-1 through calcium can lead to the protein being able to flattenthe rod, elongating the protein, and can allow fibrillin-1 to behave in anelastic nature. Fibrillin-1 can provide support to non-elastic tissues, andanchors endothelial and epithelial tissues to elastic fibres.11Calcium,when bound to fibrillin-1, is shown to protect against proteolysis fromproteases within the matrix, such as elastase and trypsin.

This is importantfor fibrillin-1 to be able to function, as cbEGF domains that bind to calciumallow fibrillin to carry out its various functions without degrading. Calcium is also importantin stabilising the fibrillin-1 structure; without calcium, microfibrils becomedistorted.8 Another function that fibrillin-1 has is to store TGF-?,which is inactive whilst bound to the fibrillin-1 within the microfibrils. TGF-? controls many cell processes including: cell proliferation,cell motility and apoptosis.

GC4 12The structure of the TB domains allows fibrillin-1 to bind to TGF-?, thus thestructure of the TB domains allows fibrillin-1 to participate in the control ofthese mechanisms.TheFBN1 gene codes for both fibrillin-1 and asprosin, which is used in glucosehomeostasis.13 It is located at 15q21.1, at base pairs 48,408,406 to48,645,788 on chromosome 15.12 The size of transcript is around 10kband the gene has 65 exons.11 Mutations in the FBN1 gene is known to causeMarfan Syndrome (MFS). MFS is an autosomal dominant disease.

Around threequarters of cases are inherited, and a quarter occur from new mutations.14There are over 3000 recorded mutations known to cause MFS,15 whichshows that the FBN1 gene is highly susceptive to genetic changes. Pointmutations are the most common mutations that take place in the gene, with theoccurrence at around 60%. Frameshifts are responsible for 13% of mutations, andsplicing errors also account for 13%.7 The mutations can be splitinto two groups; one third lead to nonsense-mediated decay, where faulty mRNAis broken down and results in a lower amount of the protein being produced, andtwo thirds leads to improper folding of the fibrillin-1 protein.7The mutations that bring about improperfolding can affect disulphide bridges, amino acid residues involved in calciumbonding or other amino acids that affect the conformation of fibrillin-1. Thesemutations change the conformation of the fibrillin-1 protein and can lower theaffinity for calcium, thus the protein is not protected from proteolysis andthe stability of the protein is disrupted. Fibrillin-1 may not be able to bindto TGF-? if the 3D shape of fibrillin-1 changes, leading to fibrillin-1 beingunable to store TGF-? within the extracellular matrix.

MFS sufferers tend tohave a delayed secretion of fibrillin-1, though some have normal secretionwhich supports that fibrillin-1 has compromised effectiveness in theextracellular environment. Some MFS sufferers have fibrillin-1 that is seen tohave undergone glycosylation which suggests that their fibrillin-1 does notleave the cell and is retained in the endoplasmic reticulum.3,16 MFScan be caused hundreds of different known mutations, so the nature of the mutation will affect the functionality andvesicular trafficking of fibrillin-1.MFS is the most common genetic diseaseaffecting connective tissue. It has a frequency of 1 in 5000 people.

14MFS sufferers tend to be taller and slenderer  thanfamily members that are not affected and have very long fingers and toes(arachnodactyly). Over half of sufferers also develop scoliosis- abnormalcurving of the spine. The sternum can protrude outwards or be sunken andfingers may be bent, as well as joint hypermobility. Spinal abnormalities aredue to TGF-? not being stored in the mutant fibrillin-1, leading to tissuesovergrowing and instability within the tissues. This can also lead tocardiovascular problems, some of which can be very serious and lifethreatening. Aortic dilation (enlargement of the aorta) or aortic aneurysm(bulging of aorta walls) can occur.

This puts the MFS sufferer at risk ofaortic dissection, where the aorta wall can rupture or tear. This is due tofragmentation and disorganisation in the elastic fibres, as tropoelastindeposition is disrupted. If the ascending aorta tears it is life threateningand requires immediate surgery. A tear in the descending aorta is not asdangerous, however still puts the vital organs at risk of reduced blood flow.Other cardiac problems include leakage of the mitral valve, causing anirregular heartbeat and chest pain. 14,17,18,19MFS can cause problems with the eyes. Nearsightedness is extremely common and often sufferers get ectopia lentis, wherethe lens detaches from the centre of the eyeball.

They can develop cataracts orglaucoma early in life, which leads to blindness if untreated. Some MFSsufferers develop pockets of air in the lung and spontaneous lung collapse.Other diseases can have very similar symptoms to MFS, however are due tomutations in genes for other very similar proteins, such as fibrillin-2. MFShas no cure as it is a genetic disease and treatments are directed towardsspecific symptoms of MFS. MFS has a high survival rate, though some moreseverely affected die in infancy.14,17,18,19Figure 1 source: https://www.sciencedirect.com/science/article/pii/S0022283698925360Figure 2 source: http://www.sciencedirect.com/science/article/pii/S0167488900000859?via%3Dihub

x

Hi!
I'm Dora!

Would you like to get a custom essay? How about receiving a customized one?

Click here