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{{STRUCTURE_3ayu|  PDB=3ayu  |  SCENE=  }}
===Crystal structure of MMP-2 active site mutant in complex with APP-drived decapeptide inhibitor===
{{ABSTRACT_PUBMED_21813640}}


==Disease==
==Crystal structure of MMP-2 active site mutant in complex with APP-drived decapeptide inhibitor==
[[http://www.uniprot.org/uniprot/MMP2_HUMAN MMP2_HUMAN]] Defects in MMP2 are the cause of Torg-Winchester syndrome (TWS) [MIM:[http://omim.org/entry/259600 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.<ref>PMID:11431697</ref><ref>PMID:15691365</ref><ref>PMID:16542393</ref> [[http://www.uniprot.org/uniprot/A4_HUMAN A4_HUMAN]] Defects in APP are the cause of Alzheimer disease type 1 (AD1) [MIM:[http://omim.org/entry/104300 104300]]. AD1 is a familial early-onset form of Alzheimer disease. It can be associated with cerebral amyloid angiopathy. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituent of these plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s), derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products such as C31 derived from APP, are also implicated in neuronal death.<ref>PMID:8476439</ref><ref>PMID:15201367</ref><ref>PMID:1671712</ref><ref>PMID:1908231</ref><ref>PMID:1678058</ref><ref>PMID:1944558</ref><ref>PMID:1925564</ref><ref>PMID:1415269</ref><ref>PMID:1303239</ref><ref>PMID:1302033</ref><ref>PMID:1303275</ref><ref>PMID:8267572</ref><ref>PMID:8290042</ref><ref>PMID:8577393</ref><ref>PMID:9328472</ref><ref>PMID:9754958</ref><ref>PMID:10097173</ref><ref>PMID:10631141</ref><ref>PMID:10665499</ref><ref>PMID:10867787</ref><ref>PMID:11063718</ref><ref>PMID:11311152</ref><ref>PMID:11528419</ref><ref>PMID:12034808</ref><ref>PMID:15365148</ref><ref>PMID:15668448</ref>  Defects in APP are the cause of cerebral amyloid angiopathy APP-related (CAA-APP) [MIM:[http://omim.org/entry/605714 605714]]. A hereditary localized amyloidosis due to amyloid-beta A4 peptide(s) deposition in the cerebral vessels. The principal clinical characteristics are recurrent cerebral and cerebellar hemorrhages, recurrent strokes, cerebral ischemia, cerebral infarction, and progressive mental deterioration. Patients develop cerebral hemorrhage because of the severe cerebral amyloid angiopathy. Parenchymal amyloid deposits are rare and largely in the form of pre-amyloid lesions or diffuse plaque-like structures. They are Congo red negative and lack the dense amyloid cores commonly present in Alzheimer disease. Some affected individuals manifest progressive aphasic dementia, leukoencephalopathy, and occipital calcifications.<ref>PMID:10821838</ref><ref>PMID:2111584</ref><ref>PMID:11409420</ref><ref>PMID:12654973</ref><ref>PMID:16178030</ref>  
<StructureSection load='3ayu' size='340' side='right'caption='[[3ayu]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 
== Structural highlights ==
==Function==
<table><tr><td colspan='2'>[[3ayu]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3AYU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3AYU FirstGlance]. <br>
[[http://www.uniprot.org/uniprot/MMP2_HUMAN 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.<ref>PMID:9476898</ref><ref>PMID:10559137</ref><ref>PMID:11029402</ref><ref>PMID:11751392</ref><ref>PMID:11710594</ref><ref>PMID:19493954</ref><ref>PMID:22509276</ref> 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.<ref>PMID:9476898</ref><ref>PMID:10559137</ref><ref>PMID:11029402</ref><ref>PMID:11751392</ref><ref>PMID:11710594</ref><ref>PMID:19493954</ref><ref>PMID:22509276</ref> 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.<ref>PMID:9476898</ref><ref>PMID:10559137</ref><ref>PMID:11029402</ref><ref>PMID:11751392</ref><ref>PMID:11710594</ref><ref>PMID:19493954</ref><ref>PMID:22509276</ref> [[http://www.uniprot.org/uniprot/A4_HUMAN A4_HUMAN]] Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1-KAT5 and inhibits Notch signaling through interaction with Numb. Couples to apoptosis-inducing pathways such as those mediated by G(O) and JIP. Inhibits G(o) alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1. Involved in copper homeostasis/oxidative stress through copper ion reduction. In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. The splice isoforms that contain the BPTI domain possess protease inhibitor activity. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and leading to mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1.<ref>PMID:9168929</ref><ref>PMID:11544248</ref><ref>PMID:11943163</ref><ref>PMID:19225519</ref><ref>PMID:19901339</ref>  Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Bind transient metals such as copper, zinc and iron. In vitro, can reduce Cu(2+) and Fe(3+) to Cu(+) and Fe(2+), respectively. Beta-amyloid 42 is a more effective reductant than beta-amyloid 40. Beta-amyloid peptides bind to lipoproteins and apolipoproteins E and J in the CSF and to HDL particles in plasma, inhibiting metal-catalyzed oxidation of lipoproteins. Beta-APP42 may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Interaction with Also bind GPC1 in lipid rafts.<ref>PMID:9168929</ref><ref>PMID:11544248</ref><ref>PMID:11943163</ref><ref>PMID:19225519</ref><ref>PMID:19901339</ref>  Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain (By similarity).<ref>PMID:9168929</ref><ref>PMID:11544248</ref><ref>PMID:11943163</ref><ref>PMID:19225519</ref><ref>PMID:19901339</ref>  The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis.<ref>PMID:9168929</ref><ref>PMID:11544248</ref><ref>PMID:11943163</ref><ref>PMID:19225519</ref><ref>PMID:19901339</ref>  N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6).<ref>PMID:9168929</ref><ref>PMID:11544248</ref><ref>PMID:11943163</ref><ref>PMID:19225519</ref><ref>PMID:19901339</ref>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2&#8491;</td></tr>
 
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
==About this Structure==
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3ayu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ayu OCA], [https://pdbe.org/3ayu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ayu RCSB], [https://www.ebi.ac.uk/pdbsum/3ayu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ayu ProSAT]</span></td></tr>
[[3ayu]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3AYU OCA].
</table>
== Disease ==
[https://www.uniprot.org/uniprot/MMP2_HUMAN MMP2_HUMAN] Defects in MMP2 are the cause of Torg-Winchester syndrome (TWS) [MIM:[https://omim.org/entry/259600 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.<ref>PMID:11431697</ref> <ref>PMID:15691365</ref> <ref>PMID:16542393</ref>  
== Function ==
[https://www.uniprot.org/uniprot/MMP2_HUMAN 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.<ref>PMID:9476898</ref> <ref>PMID:10559137</ref> <ref>PMID:11029402</ref> <ref>PMID:11751392</ref> <ref>PMID:11710594</ref> <ref>PMID:19493954</ref> <ref>PMID:22509276</ref>   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.<ref>PMID:9476898</ref> <ref>PMID:10559137</ref> <ref>PMID:11029402</ref> <ref>PMID:11751392</ref> <ref>PMID:11710594</ref> <ref>PMID:19493954</ref> <ref>PMID:22509276</ref>   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.<ref>PMID:9476898</ref> <ref>PMID:10559137</ref> <ref>PMID:11029402</ref> <ref>PMID:11751392</ref> <ref>PMID:11710594</ref> <ref>PMID:19493954</ref> <ref>PMID:22509276</ref>  


==See Also==
==See Also==
*[[Matrix metalloproteinase|Matrix metalloproteinase]]
*[[Matrix metalloproteinase 3D structures|Matrix metalloproteinase 3D structures]]
 
== References ==
==Reference==
<references/>
<ref group="xtra">PMID:021813640</ref><references group="xtra"/><references/>
__TOC__
[[Category: Gelatinase A]]
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Hashimoto, H.]]
[[Category: Large Structures]]
[[Category: Higashi, S.]]
[[Category: Hashimoto H]]
[[Category: Komatsu, K.]]
[[Category: Higashi S]]
[[Category: Miyazaki, K.]]
[[Category: Komatsu K]]
[[Category: Sato, M.]]
[[Category: Miyazaki K]]
[[Category: Takeuchi, T.]]
[[Category: Sato M]]
[[Category: Hydrolase-hydrolase inhibitor complex]]
[[Category: Takeuchi T]]
[[Category: Protease]]

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