| Structural highlights
Disease
[FINC_HUMAN] Defects in FN1 are the cause of glomerulopathy with fibronectin deposits type 2 (GFND2) [MIM:601894]; also known as familial glomerular nephritis with fibronectin deposits or fibronectin glomerulopathy. GFND is a genetically heterogeneous autosomal dominant disorder characterized clinically by proteinuria, microscopic hematuria, and hypertension that leads to end-stage renal failure in the second to fifth decade of life.[1]
Function
[FINC_HUMAN] Fibronectins bind cell surfaces and various compounds including collagen, fibrin, heparin, DNA, and actin. Fibronectins are involved in cell adhesion, cell motility, opsonization, wound healing, and maintenance of cell shape.[2] [3] [4] [5] Anastellin binds fibronectin and induces fibril formation. This fibronectin polymer, named superfibronectin, exhibits enhanced adhesive properties. Both anastellin and superfibronectin inhibit tumor growth, angiogenesis and metastasis. Anastellin activates p38 MAPK and inhibits lysophospholipid signaling.[6] [7] [8] [9]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
BACKGROUND: The process of angiogenesis (i.e. the formation of new blood vessels from pre-existing ones) is fundamental to physiological processes such as reproduction, development and repair, as well as to pathological conditions such as tumor progression, rheumathoid arthritis and ocular disorders. The oncofoetal ED-B domain, a specific marker of angiogenesis, consists of 91 amino acid residues that are inserted by alternative splicing into the fibronectin (FN) molecule. RESULTS: The NMR structure of the ED-B domain is reported and reveals important differences from other FN type III domains. A comparison of the ED-B domain with the crystal structure of a four-domain FN fragment shows the novel features of ED-B to be located in loop regions that are buried at interdomain interfaces, and which therefore largely determine the global shape of the FN molecule. The negatively charged amino acids in this highly acidic protein are uniformly distributed over the molecular surface, with the sole exception of a solvent-exposed hydrophobic patch that represents a potential specific recognition site. Epitope mapping with 82 decapeptides that span the ED-B sequence revealed that three ED-B-specific monoclonal antibodies, which selectively target newly forming blood vessels in tumor-bearing mice, bind to adjacent regions on the ED-B surface. CONCLUSIONS: The NMR structure enables the identification of a large surface area of the ED-B domain that appears to be accessible in vivo, opening up new diagnostic and therapeutic opportunities. Furthermore, the mapping of specific monoclonal antibodies to the three-dimensional structure of the ED-B domain, and their use in angiogenesis inhibition experiments, provides a basis for further investigation of the role of the ED-B domain in the formation of new blood vessels.
NMR structure of the human oncofoetal fibronectin ED-B domain, a specific marker for angiogenesis.,Fattorusso R, Pellecchia M, Viti F, Neri P, Neri D, Wuthrich K Structure. 1999 Apr 15;7(4):381-90. PMID:10196121[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Castelletti F, Donadelli R, Banterla F, Hildebrandt F, Zipfel PF, Bresin E, Otto E, Skerka C, Renieri A, Todeschini M, Caprioli J, Caruso RM, Artuso R, Remuzzi G, Noris M. Mutations in FN1 cause glomerulopathy with fibronectin deposits. Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2538-43. Epub 2008 Feb 11. PMID:18268355 doi:0707730105
- ↑ Morla A, Zhang Z, Ruoslahti E. Superfibronectin is a functionally distinct form of fibronectin. Nature. 1994 Jan 13;367(6459):193-6. PMID:8114919 doi:http://dx.doi.org/10.1038/367193a0
- ↑ Yi M, Ruoslahti E. A fibronectin fragment inhibits tumor growth, angiogenesis, and metastasis. Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):620-4. PMID:11209058 doi:10.1073/pnas.98.2.620
- ↑ Ambesi A, Klein RM, Pumiglia KM, McKeown-Longo PJ. Anastellin, a fragment of the first type III repeat of fibronectin, inhibits extracellular signal-regulated kinase and causes G(1) arrest in human microvessel endothelial cells. Cancer Res. 2005 Jan 1;65(1):148-56. PMID:15665290
- ↑ You R, Klein RM, Zheng M, McKeown-Longo PJ. Regulation of p38 MAP kinase by anastellin is independent of anastellin's effect on matrix fibronectin. Matrix Biol. 2009 Mar;28(2):101-9. doi: 10.1016/j.matbio.2009.01.003. Epub 2009, Feb 4. PMID:19379667 doi:10.1016/j.matbio.2009.01.003
- ↑ Morla A, Zhang Z, Ruoslahti E. Superfibronectin is a functionally distinct form of fibronectin. Nature. 1994 Jan 13;367(6459):193-6. PMID:8114919 doi:http://dx.doi.org/10.1038/367193a0
- ↑ Yi M, Ruoslahti E. A fibronectin fragment inhibits tumor growth, angiogenesis, and metastasis. Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):620-4. PMID:11209058 doi:10.1073/pnas.98.2.620
- ↑ Ambesi A, Klein RM, Pumiglia KM, McKeown-Longo PJ. Anastellin, a fragment of the first type III repeat of fibronectin, inhibits extracellular signal-regulated kinase and causes G(1) arrest in human microvessel endothelial cells. Cancer Res. 2005 Jan 1;65(1):148-56. PMID:15665290
- ↑ You R, Klein RM, Zheng M, McKeown-Longo PJ. Regulation of p38 MAP kinase by anastellin is independent of anastellin's effect on matrix fibronectin. Matrix Biol. 2009 Mar;28(2):101-9. doi: 10.1016/j.matbio.2009.01.003. Epub 2009, Feb 4. PMID:19379667 doi:10.1016/j.matbio.2009.01.003
- ↑ Fattorusso R, Pellecchia M, Viti F, Neri P, Neri D, Wuthrich K. NMR structure of the human oncofoetal fibronectin ED-B domain, a specific marker for angiogenesis. Structure. 1999 Apr 15;7(4):381-90. PMID:10196121
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