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Fibronectin

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FN1
Available structures
PDBOrtholog search:H0Y7Z1%20or%20B7ZLE5 PDBeH0Y7Z1,B7ZLE5 RCSB
Identifiers
AliasesFN1,CIG, ED-B, FINC, FN, FNZ, GFND, GFND2, LETS, MSF, fibronectin 1, SMDCF
External IDsOMIM:135600;MGI:95566;HomoloGene:1533;GeneCards:FN1;OMA:FN1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

2335

14268

Ensembl

ENSG00000115414

ENSMUSG00000026193

UniProt

P02751

P11276

RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)Chr 2: 215.36 – 215.44 MbChr 1: 71.62 – 71.69 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
The modular structure of fibronectin and its binding domains

Fibronectinis a high-molecular weight(~500-~600kDa)[5]glycoproteinof theextracellular matrixthat binds tomembrane-spanningreceptor proteinscalledintegrins.[6]Fibronectin also binds to other extracellular matrix proteins such ascollagen,fibrin,andheparan sulfateproteoglycans(e.g.syndecans).

Fibronectin exists as aprotein dimer,consisting of two nearly identicalmonomerslinked by a pair ofdisulfide bonds.[6]The fibronectin protein is produced from a single gene, butalternative splicingof itspre-mRNAleads to the creation of severalisoforms.

Two types of fibronectin are present invertebrates:[6]

  • soluble plasma fibronectin (formerly called "cold-insoluble globulin", or CIg) is a major protein component ofblood plasma(300 μg/ml) and is produced in theliverbyhepatocytes.
  • insoluble cellular fibronectin is a major component of the extracellular matrix. It is secreted by variouscells,primarilyfibroblasts,as a solubleprotein dimerand is then assembled into an insoluble matrix in a complex cell-mediated process.

Fibronectin plays a major role incell adhesion,growth,migration,anddifferentiation,and it is important for processes such aswound healingandembryonic development.[6]Altered fibronectinexpression,degradation,and organization has been associated with a number ofpathologies,including cancer, arthritis, andfibrosis.[7][8]

Structure[edit]

Fibronectin exists as a protein dimer, consisting of two nearly identicalpolypeptidechains linked by a pair ofC-terminaldisulfide bonds.[9]Each fibronectinsubunithas a molecular weight of ~230–~275 kDa[10]and contains three types ofmodules:type I, II, and III. All three modules are composed of two anti-parallelβ-sheetsresulting in aBeta-sandwich;however,type Iandtype IIare stabilized by intra-chain disulfide bonds, whiletype IIImodules do not contain any disulfide bonds. The absence of disulfide bonds in type III modules allows them to partially unfold under applied force.[11]

Three regions of variablesplicingoccur along the length of the fibronectinprotomer.One or both of the "extra" type III modules (EIIIA and EIIIB) may be present in cellular fibronectin, but they are never present in plasma fibronectin. A "variable" V-region exists between III14–15(the 14th and 15th type III module). The V-region structure is different from the type I, II, and III modules, and its presence and length may vary. The V-region contains the binding site forα4β1integrins. It is present in most cellular fibronectin, but only one of the two subunits in a plasma fibronectin dimer contains a V-region sequence.

The modules are arranged into several functional andprotein-bindingdomainsalong the length of a fibronectinmonomer.There are four fibronectin-binding domains, allowing fibronectin to associate with other fibronectin molecules.[9]One of these fibronectin-binding domains, I1–5,is referred to as the "assembly domain", and it is required for the initiation of fibronectin matrix assembly. Modules III9–10correspond to the "cell-binding domain" of fibronectin. TheRGD sequence(Arg–Gly–Asp) is located in III10and is the site ofcell attachmentviaα5β1andαVβ3integrins on the cell surface. The "synergy site" is in III9and has a role in modulating fibronectin's association withα5β1integrins.[12]Fibronectin also contains domains forfibrin-binding (I1–5,I10–12),collagen-binding (I6–9),fibulin-1-binding (III13–14),heparin-binding andsyndecan-binding (III12–14).[9]

Function[edit]

Fibronectin has numerous functions that ensure the normal functioning ofvertebrateorganisms.[6]It is involved incell adhesion,growth,migration,anddifferentiation.Cellular fibronectin is assembled into theextracellular matrix,an insoluble network that separates and supports theorgansandtissuesof an organism.

Fibronectin plays a crucial role inwound healing.[13][14]Along withfibrin,plasmafibronectin is deposited at the site of injury, forming ablood clotthat stops bleeding and protects the underlyingtissue.As repair of the injured tissue continues,fibroblastsandmacrophagesbegin to remodel the area, degrading the proteins that form the provisionalblood clotmatrix and replacing them with amatrixthat more resembles the normal, surrounding tissue. Fibroblasts secreteproteases,includingmatrix metalloproteinases,that digest the plasma fibronectin, and then the fibroblasts secretecellularfibronectin and assemble it into an insolublematrix.Fragmentation of fibronectin by proteases has been suggested to promote wound contraction, a critical step inwound healing.Fragmenting fibronectin further exposes its V-region, which contains the site forα4β1integrinbinding. These fragments of fibronectin are believed to enhance the binding of α4β1 integrin-expressing cells, allowing them to adhere to and forcefully contract the surrounding matrix.

Fibronectin is necessary forembryogenesis,andinactivatingthegenefor fibronectin results in early embryonic lethality.[15]Fibronectin is important for guidingcell attachmentandmigrationduringembryonic development.Inmammaliandevelopment, the absence of fibronectin leads to defects inmesodermal,neural tube,andvasculardevelopment. Similarly, the absence of a normal fibronectin matrix in developingamphibianscauses defects inmesodermalpatterning and inhibitsgastrulation.[16]

Fibronectin is also found in normal human saliva, which helps preventcolonizationof theoral cavityandpharynxbypathogenic bacteria.[17]

Matrix assembly[edit]

Cellularfibronectin is assembled into aninsolublefibrillarmatrixin a complex cell-mediated process.[18]Fibronectin matrix assembly begins when soluble, compact fibronectindimersaresecretedfrom cells, oftenfibroblasts.These soluble dimers bind toα5β1integrinreceptors on the cell surface and aid in clustering the integrins. The localconcentrationof integrin-bound fibronectin increases, allowing bound fibronectinmoleculesto more readily interact with one another. Short fibronectinfibrilsthen begin to form between adjacent cells. As matrix assembly proceeds, the soluble fibrils are converted into larger insoluble fibrils that comprise theextracellular matrix.

Fibronectin's shift fromsolubleto insoluble fibrils proceeds when cryptic fibronectin-binding sites are exposed along the length of a bound fibronectin molecule. Cells are believed to stretch fibronectin by pulling on their fibronectin-bound integrin receptors. Thisforcepartially unfolds the fibronectinligand,unmasking cryptic fibronectin-binding sites and allowing nearby fibronectin molecules to associate. This fibronectin-fibronectin interaction enables the soluble, cell-associated fibrils to branch and stabilize into an insoluble fibronectinmatrix.

A transmembrane protein,CD93,has been shown to be essential for fibronectin matrix assembly (fibrillogenesis) in human dermal blood endothelial cells.[19]As a consequence, knockdown of CD93 in these cells resulted in the disruption of the fibronectin fibrillogenesis. Moreover, the CD93 knockout mice retinas displayed disrupted fibronectin matrix at the retinal sprouting front.[19]

Role in cancer[edit]

Several morphological changes has been observed intumorsand tumor-derivedcell linesthat have been attributed to decreased fibronectinexpression,increased fibronectindegradation,and/or decreasedexpressionof fibronectin-bindingreceptors,such asα5β1integrins.[20]

Fibronectin has been implicated incarcinomadevelopment.[21]Inlung carcinoma,fibronectinexpressionis increased especially innon-small cell lung carcinoma.Theadhesionof lung carcinoma cells to fibronectin enhancestumorigenicityand confersresistancetoapoptosis-inducingchemotherapeutic agents.Fibronectin has been shown to stimulate thegonadal steroidsthat interact withvertebrateandrogen receptors,which are capable of controlling theexpressionofcyclin Dand relatedgenesinvolved incell cyclecontrol. These observations suggest that fibronectin may promote lungtumor growth/survival and resistance to therapy, and it could represent a noveltargetfor the development of newanticancer drugs.

Fibronectin 1 acts as a potentialbiomarkerforradioresistance[22]and for pan-cancer prognosis.[23]

FN1-FGFR1 fusion is frequent in phosphaturic mesenchymal tumours.[24][25]

Role in wound healing[edit]

Fibronectin has profound effects onwound healing,including the formation of proper substratum for migration and growth of cells during the development and organization ofgranulation tissue,as well as remodeling and resynthesis of the connective tissue matrix.[26]The biological significance of fibronectinin vivowas studied during the mechanism of wound healing.[26]Plasma fibronectin levels are decreased in acute inflammation or following surgical trauma and in patients withdisseminated intravascular coagulation.[27]

Fibronectin is located in the extracellular matrix of embryonic and adult tissues (not in thebasement membranesof the adult tissues), but may be more widely distributed in inflammatory lesions. During blood clotting, the fibronectin remains associated with the clot, covalently cross-linked tofibrinwith the help ofFactor XIII(fibrin-stabilizing factor).[28][29]Fibroblastsplay a major role in wound healing by adhering to fibrin. Fibroblast adhesion to fibrin requires fibronectin, and was strongest when the fibronectin was cross-linked to the fibrin. Patients with Factor XIII deficiencies display impairment in wound healing as fibroblasts don't grow well in fibrin lacking Factor XIII. Fibronectin promotes particlephagocytosisby bothmacrophagesand fibroblasts. Collagen deposition at the wound site by fibroblasts takes place with the help of fibronectin. Fibronectin was also observed to be closely associated with the newly depositedcollagenfibrils. Based on the size andhistologicalstaining characteristics of the fibrils, it is likely that at least in part they are composed of type III collagen (reticulin). Anin vitrostudy with native collagen demonstrated that fibronectin binds to type III collagen rather than other types.[30]

In vivovsin vitro[edit]

Plasma fibronectin, which is synthesized byhepatocytes,[31]and fibronectin synthesized byculturedfibroblastsare similar but not identical; immunological, structural, and functional differences have been reported.[32]It is likely that these differences result from differential processing of a single nascent mRNA. Nevertheless, plasma fibronectin can be insolubilized into the tissueextracellular matrixin vitroandin vivo.Both plasma and cellular fibronectins in the matrix form high molecular weight,disulfide-bondedmultimers.The mechanism of formation of these multimers is not presently known. Plasma fibronectin has been shown to contain two freesulfhydrylsper subunit (X), and cellular fibronectin has been shown to contain at least one. These sulfhydryls probably are buried within thetertiary structure,because sulfhydryls are exposed when the fibronectin is denatured. Such denaturation results in the oxidation of free sulfhydryls and formation of disulfide-bonded fibronectin multimers. This has led to speculation that the free sulfhydryls may be involved in formation of disulfide-bonded fibronectin multimers in the extracellular matrix. Consistent with this, sulfhydryl modification of fibronectin withN-ethylmaleimideprevents binding to cell layers.Trypticcleavage patterns of multimeric fibronectin do not reveal the disulfide-bonded fragments that would be expected if multimerization involved one or both of the free sulfhydryls. The free sulfhydryls of fibronectin are not required for the binding of fibronectin to the cell layer or for its subsequent incorporation into the extracellular matrix. Disulfide-bonded multimerization of fibronectin in the cell layer occurs by disulfide bond exchange in the disulfide-richamino-terminalone-third of the molecule.[32]

Fibronectin genetic variation as a protective factor against Alzheimer's disease[edit]

A specific genetic variation in Fibronectin gene was shown to reduce the risk of developing Alzheimer's disease in a multicenter, multiethnic genetic epidemiology and functional genomics study. This effect is believed to be through enhancing the brain's ability to clear the toxic waste and protein accummulation through blood-brain-barrier.[33]


Interactions[edit]

Besides integrin, fibronectin binds to many other host and non-host molecules. For example, it has been shown to interact with proteins suchfibrin,tenascin,TNF-α, BMP-1, rotavirus NSP-4, and many fibronectin-binding proteins from bacteria (like FBP-A; FBP-B on the N-terminal domain), as well as theglycosaminoglycan,heparan sulfate.

Fibronectin has been shown tointeractwith:

See also[edit]

References[edit]

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Further reading[edit]

External links[edit]

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