1cxw

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THE SECOND TYPE II MODULE FROM HUMAN MATRIX METALLOPROTEINASE 2

Structural highlights

1cxw is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Solution NMR, 50 models
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

MMP2_HUMAN Defects in MMP2 are the cause of Torg-Winchester syndrome (TWS) [MIM:259600; also known as multicentric osteolysis nodulosis and arthropathy (MONA). TWS is an autosomal recessive osteolysis syndrome. It is severe with generalized osteolysis and osteopenia. Subcutaneous nodules are usually absent. Torg-Winchester syndrome has been associated with a number of additional features including coarse face, corneal opacities, patches of thickened, hyperpigmented skin, hypertrichosis and gum hypertrophy. However, these features are not always present and have occasionally been observed in other osteolysis syndromes.[1] [2] [3]

Function

MMP2_HUMAN Ubiquitinous metalloproteinase that is involved in diverse functions such as remodeling of the vasculature, angiogenesis, tissue repair, tumor invasion, inflammation, and atherosclerotic plaque rupture. As well as degrading extracellular matrix proteins, can also act on several nonmatrix proteins such as big endothelial 1 and beta-type CGRP promoting vasoconstriction. Also cleaves KISS at a Gly-|-Leu bond. Appears to have a role in myocardial cell death pathways. Contributes to myocardial oxidative stress by regulating the activity of GSK3beta. Cleaves GSK3beta in vitro.[4] [5] [6] [7] [8] [9] [10] PEX, the C-terminal non-catalytic fragment of MMP2, posseses anti-angiogenic and anti-tumor properties and inhibits cell migration and cell adhesion to FGF2 and vitronectin. Ligand for integrinv/beta3 on the surface of blood vessels.[11] [12] [13] [14] [15] [16] [17] Isoform 2: Mediates the proteolysis of CHUK/IKKA and initiates a primary innate immune response by inducing mitochondrial-nuclear stress signaling with activation of the pro-inflammatory NF-kappaB, NFAT and IRF transcriptional pathways.[18] [19] [20] [21] [22] [23] [24]

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: Matrix metalloproteinase 2 (MMP-2, gelatinase A, 72 kDa type IV collagenase) has an important role in extracellular matrix degradation during cell migration and tissue remodeling. It is involved in development, inflammation, wound healing, tumor invasion, metastasis and other physiological and pathological processes. The enzyme cleaves several types of collagen, elastin, fibronectin and laminin. Binding to collagen is mediated by three repeats homologous to fibronectin type II modules, which are inserted in the catalytic domain in proximity to the active site. RESULTS: We have determined the NMR solution structure of the second type II module from human MMP-2 (col-2). The module exhibits a typical type II fold with two short double-stranded antiparallel beta sheets and three large loops packed around a cluster of conserved aromatic residues. Backbone amide dynamics, derived from (15)N relaxation experiments, correlate well with solvent accessibility and intramolecular hydrogen bonding. A synthetic peptide with the collagen consensus sequence, (Pro-Pro-Gly)(6), is shown to interact with the module. CONCLUSIONS: Spectral perturbations induced by (Pro-Pro-Gly)(6) binding reveal the region involved in the interaction of col-2 with collagen. The binding surface comprises exposed aromatic residues Phe21, Tyr38, Trp40, Tyr47, Tyr53 and Phe55, and the neighboring Gly33-Gly37 segment.

The second type II module from human matrix metalloproteinase 2: structure, function and dynamics.,Briknarova K, Grishaev A, Banyai L, Tordai H, Patthy L, Llinas M Structure. 1999 Oct 15;7(10):1235-45. PMID:10545322[25]

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

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Citations
6 reviews cite this structure
Gelatinase-mediated migration and invasion of cancer cells.
Björklund et al. (2005)
5 more
22 other articles
No citations found

See Also

References

  1. ↑ Martignetti JA, Aqeel AA, Sewairi WA, Boumah CE, Kambouris M, Mayouf SA, Sheth KV, Eid WA, Dowling O, Harris J, Glucksman MJ, Bahabri S, Meyer BF, Desnick RJ. Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome. Nat Genet. 2001 Jul;28(3):261-5. PMID:11431697 doi:10.1038/90100
  2. ↑ Zankl A, Bonafe L, Calcaterra V, Di Rocco M, Superti-Furga A. Winchester syndrome caused by a homozygous mutation affecting the active site of matrix metalloproteinase 2. Clin Genet. 2005 Mar;67(3):261-6. PMID:15691365 doi:10.1111/j.1399-0004.2004.00402.x
  3. ↑ Rouzier C, Vanatka R, Bannwarth S, Philip N, Coussement A, Paquis-Flucklinger V, Lambert JC. A novel homozygous MMP2 mutation in a family with Winchester syndrome. Clin Genet. 2006 Mar;69(3):271-6. PMID:16542393 doi:CGE584
  4. ↑ Brooks PC, Silletti S, von Schalscha TL, Friedlander M, Cheresh DA. Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with integrin binding activity. Cell. 1998 Feb 6;92(3):391-400. PMID:9476898
  5. ↑ Fernandez-Patron C, Radomski MW, Davidge ST. Vascular matrix metalloproteinase-2 cleaves big endothelin-1 yielding a novel vasoconstrictor. Circ Res. 1999 Nov 12;85(10):906-11. PMID:10559137
  6. ↑ Fernandez-Patron C, Stewart KG, Zhang Y, Koivunen E, Radomski MW, Davidge ST. Vascular matrix metalloproteinase-2-dependent cleavage of calcitonin gene-related peptide promotes vasoconstriction. Circ Res. 2000 Oct 13;87(8):670-6. PMID:11029402
  7. ↑ Bello L, Lucini V, Carrabba G, Giussani C, Machluf M, Pluderi M, Nikas D, Zhang J, Tomei G, Villani RM, Carroll RS, Bikfalvi A, Black PM. Simultaneous inhibition of glioma angiogenesis, cell proliferation, and invasion by a naturally occurring fragment of human metalloproteinase-2. Cancer Res. 2001 Dec 15;61(24):8730-6. PMID:11751392
  8. ↑ Chattopadhyay N, Mitra A, Frei E, Chatterjee A. Human cervical tumor cell (SiHa) surface alphavbeta3 integrin receptor has associated matrix metalloproteinase (MMP-2) activity. J Cancer Res Clin Oncol. 2001 Nov;127(11):653-8. PMID:11710594
  9. ↑ Kandasamy AD, Schulz R. Glycogen synthase kinase-3beta is activated by matrix metalloproteinase-2 mediated proteolysis in cardiomyoblasts. Cardiovasc Res. 2009 Sep 1;83(4):698-706. doi: 10.1093/cvr/cvp175. Epub 2009 Jun , 3. PMID:19493954 doi:10.1093/cvr/cvp175
  10. ↑ Lovett DH, Mahimkar R, Raffai RL, Cape L, Maklashina E, Cecchini G, Karliner JS. A novel intracellular isoform of matrix metalloproteinase-2 induced by oxidative stress activates innate immunity. PLoS One. 2012;7(4):e34177. doi: 10.1371/journal.pone.0034177. Epub 2012 Apr 3. PMID:22509276 doi:10.1371/journal.pone.0034177
  11. ↑ Brooks PC, Silletti S, von Schalscha TL, Friedlander M, Cheresh DA. Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with integrin binding activity. Cell. 1998 Feb 6;92(3):391-400. PMID:9476898
  12. ↑ Fernandez-Patron C, Radomski MW, Davidge ST. Vascular matrix metalloproteinase-2 cleaves big endothelin-1 yielding a novel vasoconstrictor. Circ Res. 1999 Nov 12;85(10):906-11. PMID:10559137
  13. ↑ Fernandez-Patron C, Stewart KG, Zhang Y, Koivunen E, Radomski MW, Davidge ST. Vascular matrix metalloproteinase-2-dependent cleavage of calcitonin gene-related peptide promotes vasoconstriction. Circ Res. 2000 Oct 13;87(8):670-6. PMID:11029402
  14. ↑ Bello L, Lucini V, Carrabba G, Giussani C, Machluf M, Pluderi M, Nikas D, Zhang J, Tomei G, Villani RM, Carroll RS, Bikfalvi A, Black PM. Simultaneous inhibition of glioma angiogenesis, cell proliferation, and invasion by a naturally occurring fragment of human metalloproteinase-2. Cancer Res. 2001 Dec 15;61(24):8730-6. PMID:11751392
  15. ↑ Chattopadhyay N, Mitra A, Frei E, Chatterjee A. Human cervical tumor cell (SiHa) surface alphavbeta3 integrin receptor has associated matrix metalloproteinase (MMP-2) activity. J Cancer Res Clin Oncol. 2001 Nov;127(11):653-8. PMID:11710594
  16. ↑ Kandasamy AD, Schulz R. Glycogen synthase kinase-3beta is activated by matrix metalloproteinase-2 mediated proteolysis in cardiomyoblasts. Cardiovasc Res. 2009 Sep 1;83(4):698-706. doi: 10.1093/cvr/cvp175. Epub 2009 Jun , 3. PMID:19493954 doi:10.1093/cvr/cvp175
  17. ↑ Lovett DH, Mahimkar R, Raffai RL, Cape L, Maklashina E, Cecchini G, Karliner JS. A novel intracellular isoform of matrix metalloproteinase-2 induced by oxidative stress activates innate immunity. PLoS One. 2012;7(4):e34177. doi: 10.1371/journal.pone.0034177. Epub 2012 Apr 3. PMID:22509276 doi:10.1371/journal.pone.0034177
  18. ↑ Brooks PC, Silletti S, von Schalscha TL, Friedlander M, Cheresh DA. Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with integrin binding activity. Cell. 1998 Feb 6;92(3):391-400. PMID:9476898
  19. ↑ Fernandez-Patron C, Radomski MW, Davidge ST. Vascular matrix metalloproteinase-2 cleaves big endothelin-1 yielding a novel vasoconstrictor. Circ Res. 1999 Nov 12;85(10):906-11. PMID:10559137
  20. ↑ Fernandez-Patron C, Stewart KG, Zhang Y, Koivunen E, Radomski MW, Davidge ST. Vascular matrix metalloproteinase-2-dependent cleavage of calcitonin gene-related peptide promotes vasoconstriction. Circ Res. 2000 Oct 13;87(8):670-6. PMID:11029402
  21. ↑ Bello L, Lucini V, Carrabba G, Giussani C, Machluf M, Pluderi M, Nikas D, Zhang J, Tomei G, Villani RM, Carroll RS, Bikfalvi A, Black PM. Simultaneous inhibition of glioma angiogenesis, cell proliferation, and invasion by a naturally occurring fragment of human metalloproteinase-2. Cancer Res. 2001 Dec 15;61(24):8730-6. PMID:11751392
  22. ↑ Chattopadhyay N, Mitra A, Frei E, Chatterjee A. Human cervical tumor cell (SiHa) surface alphavbeta3 integrin receptor has associated matrix metalloproteinase (MMP-2) activity. J Cancer Res Clin Oncol. 2001 Nov;127(11):653-8. PMID:11710594
  23. ↑ Kandasamy AD, Schulz R. Glycogen synthase kinase-3beta is activated by matrix metalloproteinase-2 mediated proteolysis in cardiomyoblasts. Cardiovasc Res. 2009 Sep 1;83(4):698-706. doi: 10.1093/cvr/cvp175. Epub 2009 Jun , 3. PMID:19493954 doi:10.1093/cvr/cvp175
  24. ↑ Lovett DH, Mahimkar R, Raffai RL, Cape L, Maklashina E, Cecchini G, Karliner JS. A novel intracellular isoform of matrix metalloproteinase-2 induced by oxidative stress activates innate immunity. PLoS One. 2012;7(4):e34177. doi: 10.1371/journal.pone.0034177. Epub 2012 Apr 3. PMID:22509276 doi:10.1371/journal.pone.0034177
  25. ↑ Briknarova K, Grishaev A, Banyai L, Tordai H, Patthy L, Llinas M. The second type II module from human matrix metalloproteinase 2: structure, function and dynamics. Structure. 1999 Oct 15;7(10):1235-45. PMID:10545322

Contents


PDB ID 1cxw

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