Matrix metalloproteinase: Difference between revisions
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== Function == | == Function == | ||
'''Matrix metalloproteinases''' (MMP) are Zinc-dependent endopeptidases. MMP degrades extracellular matrix proteins | '''Matrix metalloproteinases''' (MMP) are Zinc-dependent endopeptidases. MMP degrades extracellular matrix proteins. They are inhibited by proteases called tissue inhibitors of metalloproteinase (TIMP). The pro-MMP contains a pro-peptide which must be removed to render the MMP active<ref>PMID:10419448</ref>. See details in<br /> | ||
* [[Matrix Metalloproteinase 12]]<br /> | * [[Matrix Metalloproteinase 12]]<br /> | ||
* [[Molecular Playground/MMP9]]<br /> | * [[Molecular Playground/MMP9]]<br /> | ||
* [[Molecular Playground/ | * [[Molecular Playground/MMP9]]<br /> | ||
* [[Matrix metalloproteinases]]<br /> | * [[Matrix metalloproteinases]]<br /> | ||
* [[Metalloproteases]]<br /> | * [[Metalloproteases]]<br /> | ||
* [[Atragin]] for MMP adamalysin<br /> | * [[Atragin]] for MMP adamalysin<br /> | ||
* [[MT1-MMP-TIMP-1 complex]]<br />. | * [[MT1-MMP-TIMP-1 complex]]<br />. | ||
MMPs are produced by 28 different genes and are classified according to their protein substrates.<br /> | |||
* MMP1 cleaves collagens I, II, III, VII and X.<br /> | |||
* MMP2 cleaves collagen IV and denatured collagen.<br /> | |||
* MMP3 cleaves the core protein of aggrecan and plasminogen activator.<br /> | |||
* MMP7 cleaves proteoglycans, fibronectin, elastin and casein.<br /> | |||
* MMP8 cleaves aggrecan.<br /> | |||
* MMP9 cleaves gelatin. See details in [[Molecular Playground/MMP9]]<br /> | |||
* MMP10 cleaves collagens III, IV, V, fibronectin,gelatin and aggrecan.<br /> | |||
* MMP11 cleaves peptides in human tumors.<br /> | |||
* MMP12 cleaves collagens I and III. See details in [[Matrix Metalloproteinase 12]] <br /> | |||
* MMP13 cleaves collagen II and laminin-5 γ2.<br /> | |||
* MMP14 is a membrane-type MMP which cleaves aggrecan. See details in [[Molecular Playground/MMP14]]<br /> | |||
== Relevance == | == Relevance == | ||
MMPs have a role in cancer progression<ref>PMID:21087457</ref>. MMP-8, MMP-9, MMP-13 and MMP-14 have a role in periodontal diseases<ref>PMID:8315570</ref>. | MMPs have a role in cancer progression<ref>PMID:21087457</ref>. MMP-2 and MMP-9 secretion is elevated in ovarian cancer and are associated with poor prognosis<ref>PMID:19360311</ref>. MMP-8, MMP-9, MMP-13 and MMP-14 have a role in periodontal diseases<ref>PMID:8315570</ref>. | ||
{{Clear}} | {{Clear}} | ||
Revision as of 11:49, 19 April 2016
FunctionMatrix metalloproteinases (MMP) are Zinc-dependent endopeptidases. MMP degrades extracellular matrix proteins. They are inhibited by proteases called tissue inhibitors of metalloproteinase (TIMP). The pro-MMP contains a pro-peptide which must be removed to render the MMP active[1]. See details in
MMPs are produced by 28 different genes and are classified according to their protein substrates.
RelevanceMMPs have a role in cancer progression[2]. MMP-2 and MMP-9 secretion is elevated in ovarian cancer and are associated with poor prognosis[3]. MMP-8, MMP-9, MMP-13 and MMP-14 have a role in periodontal diseases[4]. MT1-MMP-TIMP-1 complexThe human matrix metalloproteinases (MMPs) family comprises a large group of structurally homologous zinc-dependent endopeptidases (e.g. (darkmagenta) and (magenta), ) that perform a wide variety of biological roles. In general, the MMPs are inhibited unselectively by all four known tissue inhibitors of metalloproteinases (TIMPs 1-4) which have 40-50% sequence identity. For example, can form complex with (1uea, colored orange). (cyan) is mainly composed of the N-terminal segment that approaches the active site, the AB loop (Thr33-Tyr35), the CD loop (Ala65-Cys70), and the EF loop (Thr97-Ser100). The pivotal residue, threonine 98 (Thr98), is shown as red sticks. In general, (Cys1-Ser68, Val69-Met66, Gly71-Met66, Cys70-Glu67, and Cys70-Thr98) are intimately involved in the conformational stability of TIMP binding interface when bound to MMP. (darkmagenta) also forms complex with (2j0t, colored orange), producing as well as . This network of hydrogen bonds stabilizes the CD and EF loops that compose the binding interface. Importantly, the . However, this MT1-MMP-WT-TIMP-1 complex is not tight-binding. MT1-MMP is unique since even though it exhibits high structural homology to all MMPs, it is not inhibited by TIMP-1, (1bqq). (mutant TIMP-1 is colored in yellow with T98L shown in red) transformed TIMP-1 into a high affinity inhibitor of MT1-MMP (3ma2). WT-TIMP-1, WT-TIMP-2, and TIMP-1 T98L mutant have kinetic dissociation binding constant (KD) 1.53 x 10-6, 5.61 x 10-8, and 8.70 x 10-8, respectively. So, KD of WT-TIMP-2 is 2 orders of magnitude smaller than that of WT-TIMP-1, indicating the weak affinity between MT1-MMP and WT-TIMP-1. The TIMP-1 T98L mutant regained high-affinity binding to MT1-MMP, resulting in a 2 order of magnitude decrease in KD, similar to the case for WT-TIMP-2, the in vivo inhibitor of MT1-MMP. The overall structures of the complexes of MT1-MMP-WT-TIMP-1 and MT1-MMP-mutant-T98L-TIMP-1 are . Even the structure of MT3-MMP-WT-TIMP-1 is (with wild-type and TIMP-1 T98L mutant). , which is situated near the MT1-MMP . So, this T98L replacement may stabilize the entire area by establishing a strong hydrophobic core upon binding to the enzyme. However, it seems unlikely that these additional bonds could account for the entire binding effect between MT1-MMP and TIMP-1. Statistical analysis of the stabilities in the TIMP-1 T98L mutant reveals that the hydrogen bonds network in mutant form is significantly more stable than that in WT-TIMP-1. Mutations that enhance hydrogen bond stability contribute to the stability of the bound-like, less flexible, conformation of TIMP-1, which eventually results in increasing binding affinity for MT1-MMP. Thus, mutation affected the instrinsic dynamics of the inhibitor rather than its structure, thereby facilitating the interaction [5]. |
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3D structures of matrix metalloproteinase3D structures of matrix metalloproteinase
Updated on 19-April-2016
ReferencesReferences
- ↑ Nagase H, Woessner JF Jr. Matrix metalloproteinases. J Biol Chem. 1999 Jul 30;274(31):21491-4. PMID:10419448
- ↑ Gialeli C, Theocharis AD, Karamanos NK. Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J. 2011 Jan;278(1):16-27. doi: 10.1111/j.1742-4658.2010.07919.x. Epub 2010, Nov 19. PMID:21087457 doi:http://dx.doi.org/10.1111/j.1742-4658.2010.07919.x
- ↑ Roomi MW, Monterrey JC, Kalinovsky T, Rath M, Niedzwiecki A. Patterns of MMP-2 and MMP-9 expression in human cancer cell lines. Oncol Rep. 2009 May;21(5):1323-33. PMID:19360311
- ↑ Birkedal-Hansen H. Role of matrix metalloproteinases in human periodontal diseases. J Periodontol. 1993 May;64(5 Suppl):474-84. PMID:8315570 doi:http://dx.doi.org/10.1902/jop.1993.64.5s.474
- ↑ Grossman M, Tworowski D, Dym O, Lee MH, Levy Y, Murphy G, Sagi I. Intrinsic protein flexibility of endogenous protease inhibitor TIMP-1 controls its binding interface and effects its function. Biochemistry. 2010 Jun 14. PMID:20545310 doi:10.1021/bi902141x