1fnh

CRYSTAL STRUCTURE OF HEPARIN AND INTEGRIN BINDING SEGMENT OF HUMAN FIBRONECTINCRYSTAL STRUCTURE OF HEPARIN AND INTEGRIN BINDING SEGMENT OF HUMAN FIBRONECTIN

Structural highlights

1fnh is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.8Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

The crystal structure of human fibronectin (FN) type III repeats 12-14 reveals the primary heparin-binding site, a clump of positively charged residues in FN13, and a putative minor site approximately 60 A away in FN14. The IDAPS motif implicated in integrin alpha4beta1 binding is at the FN13-14 junction, rendering the critical Asp184 inaccessible to integrin. Asp184 clamps the BC loop of FN14, whose sequence (PRARI) is reminiscent of the synergy sequence (PHSRN) of FN9. Mutagenesis studies prompted by this observation reveal that both arginines of the PRARI sequence are important for alpha4beta1 binding to FN12-14. The PRARI motif may represent a new class of integrin-binding sites. The spatial organization of the binding sites suggests that heparin and integrin may bind in concert.

Crystal structure of a heparin- and integrin-binding segment of human fibronectin.,Sharma A, Askari JA, Humphries MJ, Jones EY, Stuart DI EMBO J. 1999 Mar 15;18(6):1468-79. PMID:10075919^[10]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
↑ Sharma A, Askari JA, Humphries MJ, Jones EY, Stuart DI. Crystal structure of a heparin- and integrin-binding segment of human fibronectin. EMBO J. 1999 Mar 15;18(6):1468-79. PMID:10075919 doi:10.1093/emboj/18.6.1468

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OCA

[1] 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

[2] 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

[3] 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

[4] 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

[5] 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

[6] 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

[7] 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

[8] 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

[9] 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

[10] Sharma A, Askari JA, Humphries MJ, Jones EY, Stuart DI. Crystal structure of a heparin- and integrin-binding segment of human fibronectin. EMBO J. 1999 Mar 15;18(6):1468-79. PMID:10075919 doi:10.1093/emboj/18.6.1468

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