1j7m

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The Third Fibronectin Type II Module from Human Matrix Metalloproteinase 2The Third Fibronectin Type II Module from Human Matrix Metalloproteinase 2

Structural highlights

1j7m 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

Human matrix metalloproteinase-2 (MMP-2) contains an array of three fibronectin type II (FII) modules postulated to interact with gelatin (denatured collagen). Here, we verify that the NMR solution structure of the third FII repeat (COL-3) is similar to that of the second FII repeat (COL-2); characterize its ligand-binding properties; and derive dynamics properties and relative orientation in solution for the two domains of the COL-23 fragment, a construct comprising COL-2 and COL-3 in tandem, with each domain possessing a putative collagen-binding site. Interaction of the synthetic gelatin-like octadecapeptide (Pro-Pro-Gly)(6) (PPG6) with COL-3 is weaker than with COL-2. We found that a synthetic peptide comprising segment 33-42 (peptide 33-42) from the MMP-2 prodomain interacts with COL-3 and, albeit with lower affinity, with COL-2 in a way that mimics PPG6 binding. COL-3 strongly prefers peptide 33-42 over PPG6, which suggests that intramolecular interactions with the prodomain could modulate binding of pro-MMP-2 to its gelatin substrate. In COL-23, the two modules retain their structural individuality and tumble independently. Overall, the NMR data indicate that the relative orientation of the modules in COL-23 is not fixed in solution, that the modules do not interact with one another, and that COL-23 is rather flexible. The binding sites face opposite each other, and their responses to, and normalized affinities for, the longer ligand PPG12 are virtually identical to those of the individual domains for PPG6, thus precluding co- operativity, although they may interact simultaneously with multiple sites of the extracellular matrix.

Gelatin-binding region of human matrix metalloproteinase-2: solution structure, dynamics, and function of the COL-23 two-domain construct.,Briknarova K, Gehrmann M, Banyai L, Tordai H, Patthy L, Llinas M J Biol Chem. 2001 Jul 20;276(29):27613-21. Epub 2001 Apr 24. PMID:11320090[25]

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

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, Gehrmann M, Banyai L, Tordai H, Patthy L, Llinas M. Gelatin-binding region of human matrix metalloproteinase-2: solution structure, dynamics, and function of the COL-23 two-domain construct. J Biol Chem. 2001 Jul 20;276(29):27613-21. Epub 2001 Apr 24. PMID:11320090 doi:10.1074/jbc.M101105200
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