| Structural highlights
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]
Publication Abstract from PubMed
Unlike other synthetic or physiological inhibitors for matrix metalloproteinases (MMPs), the beta-amyloid precursor protein-derived inhibitory peptide (APP-IP) having ISYGNDALMP sequence has a high selectivity toward MMP-2. Our previous study identified amino acid residues of MMP-2 essential for its selective inhibition by APP-IP, and also demonstrated that the N to C direction of the decapeptide inhibitor relative to the substrate-binding cleft of MMP-2 is opposite to that of substrate. However, detailed interactions between the two molecules remained to be clarified. Here, we determined the crystal structure of the catalytic domain of MMP-2 in complex with APP-IP. We found that APP-IP in the complex is indeed embedded into the substrate-binding cleft of the catalytic domain in the N to C direction opposite to that of substrate. With the crystal structure, it was first clarified that the aromatic side chain of Tyr(3) of the inhibitor is accommodated into the S1' pocket of the protease, and the carboxylate group of Asp(6) of APP-IP coordinates bidentately to the catalytic zinc of the enzyme. The Ala(7) to Pro(10) and Tyr(3) to Ile(1) strands of the inhibitor extend into the non-prime and the prime sides of the cleft, respectively. Therefore, the decapeptide inhibitor has long-range contact with the substrate-binding cleft of the protease. This mode of interaction is probably essential for the high MMP-2-selectivity of the inhibitor, because MMPs share a common architecture in the vicinity of the catalytic center but whole structures of their substrate-binding clefts have sufficient variety for the inhibitor to distinguish MMP-2 from other MMPs.
Structural basis for matrix metalloproteinase-2 (MMP-2)-selective inhibitory action of {beta}-amyloid precursor protein-derived inhibitor.,Hashimoto H, Takeuchi T, Komatsu K, Miyazaki K, Sato M, Higashi S J Biol Chem. 2011 Aug 3. PMID:21813640[25]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Hashimoto H, Takeuchi T, Komatsu K, Miyazaki K, Sato M, Higashi S. Structural basis for matrix metalloproteinase-2 (MMP-2)-selective inhibitory action of {beta}-amyloid precursor protein-derived inhibitor. J Biol Chem. 2011 Aug 3. PMID:21813640 doi:10.1074/jbc.M111.264176
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