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14-September-2008 18:02:49 - Matrix metalloproteinase Cell surface-associated MT1-MMP MMP14, Green fluorescent protein GFP fused to the C-term produces a signal on the surface of the cell Cell surface-associated MT1-MMP MMP14, Green fluorescent protein GFP fused to the C-term produces a signal on the surface of the cell1 Matrix metalloproteinases MMPs are zinc-dependent endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs belong to a larger family of proteases known as the metzincin superfamily. Collectively they are capable of degrading all kinds of extracellular matrix proteins, but also can process a number of bioactive molecules. They are known to be involved in the cleavage of cell surface receptors, the release of apoptotic ligands such as the FAS ligand, and chemokine in/activation. MMPs are also thought to play a major role on cell behaviors such as cell proliferation, migration adhesion/dispersion, differentiation, angiogenesis, apoptosis and host defense. They were first described in vertebrates 1962, including Homo sapiens, but have since been found in invertebrates and plants. They are distinguished from other endopeptidases by their dependence on metal ions as cofactors, their ability to degrade extracellular matrix, and their specific evolutionary DNA sequence. Contents 1 History 2 Structure 2.1 The pro-peptide 2.2 The catalytic domain 2.3 The hinge region 2.4 The haemopexin-like C-terminal domain 2.5 Catalytic mechanism 3 Classification 3.1 Evolutionary 3.2 Functional 3.3 Genes 4 Function 5 Activation 6 Inhibitors 7 Pharmacology 8 References 9 External links History Initially, MMPs were described by Jerome Gross and Charles Lapiere 1962 who observed enzymatic activity collagen triple helix degradation during tadpole tail metamorphosis.2 Therefore, the enzyme was named interstitial collagenase MMP-1. Later it was purified from human skin 1968,3 and was recognized to be synthesized as a zymogen.4 The cysteine switch was described in 1990.5 Structure The MMPs share a common domain structure. The three common domains are the pro-peptide, the catalytic domain and the haemopexin-like C-terminal domain which is linked to the catalytic domain by a flexible hinge region. The pro-peptide The MMPs are initially synthesized as inactive zymogens with a pro-peptide domain that must be removed before the enzyme is active. The pro-peptide domain is part of the cysteine switch. This contains a conserved cysteine residue which interacts with the zinc in the active site and prevents binding and cleavage of the substrate keeping the enzyme in an inactive form. In the majority of the MMPs, the cysteine residue is in the conserved sequence PRCGxPD. Some MMPs have a prohormone convertase cleavage site Furin-like as part of this domain which, when cleaved, activates the enzyme. MMP-23A and MMP-23B include a transmembrane segment in this domain.6 The catalytic domain X-ray crystallographic structures of several MMP catalytic domains have shown that this domain is an oblate sphere measuring 35 x 30 x 30 Å 3.5 x 3 x 3 nm. The active site is a 20 Å 2 nm groove that runs across the catalytic domain. In the part of the catalytic domain forming the active site there is a catalytically important Zn2+ ion, which is bound by three histidine residues found in the conserved sequence HExxHxxGxxH. Hence, this sequence is a zinc-binding motif. The gelatinases, such as MMP-2, incorporate Fibronectin type II modules inserted immediately before in the zinc-binding motif in the catalytic domain.7 The hinge region The catalytic domain is connected to the C-terminal domain by a flexible hinge or linker region. This is up to 75 amino acids long, and has no determinable structure. The haemopexin-like C-terminal domain The C-terminal domain has structural similarities to the serum protein haemopexin. It has a four bladed β-propeller structure. β-propeller structures provide a large flat surface which is thought to be involved in protein-protein interactions. This determines substrate specificity and is the site for interaction with TIMP's tissue inhibitor of metalloproteinases. The haemopexin-like domain is absent in MMP-7, MMP-23, MMP-26 and the plant and nematode. MT-MMPs are anchored to the plasma membrane via a transmembrane or a GPI-anchoring domain. Catalytic mechanism There are three catalytic mechanisms published. In the first mechanism, Browner M.F. and colleagues8 proposed the base-catalysis mechanism, carried out by the conserved glutamate residue and the Zn2+ ion. In the second mechanism, the Matthews-mechanism, Kester and Matthews9 suggested an interaction between a water molecule and the Zn2+ ion during the acid-base catalysis. In the third mechanism, the Manzetti-mechanism, Manzetti Sergio and colleagues10 provided evidence that a coordination between water and zinc during catalysis was unlikely, and suggested a third mechanism wherein a histidine from the HExxHxxGxxH-motif participates in catalysis by allowing the Zn2+ ion to assume a quasi-penta coordinated state, via its dissociation from it. In this state, the Zn2+ ion is coordinated with the two oxygen atoms from the catalytic glutamic acid, the substrate's carbonyl oxygen atom, and the two histidine residues, and can polarize the glutamic acid's oxygen atom, proximate the scissile bond, and induce it to act as reversible electron donor. This forms an oxyanion transition state. At this stage, a water molecule acts on the dissociated scissile bond and completes the hydrolyzation of the substrate. Classification The MMPs can be subdivided in different ways. Evolutionary Use of bioinformatic methods to compare the primary sequences of the MMPs suggest the following evolutionary groupings of the MMPs: MMP-19 MMPs 11, 14, 15, 16 and 17 MMP-2 and MMP-9 all the other MMPs Analysis of the catalytic domains in isolation suggests that the catalytic domains evolved further once the major groups had differentiated, as is also indicated by the substrate specificities of the enzymes. Functional The most commonly used groupings by researchers in MMP biology are based partly on historical assessment of the substrate specificity of the MMP and partly on the cellular localisation of the MMP. These groups are the collagenases, the gelatinases, the stromelysins, and the membrane type MMPs MT-MMPs. The collagenases are capable of degrading triple-helical fibrillar collagens into distinctive 3/4 and 1/4 fragments. These collagens are the major components of bone and cartilage, and MMPs are the only known mammalian enzymes capable of degrading them. Traditionally, the collagenases are #1, #8, #13, and #18. In addition, #14 has also been shown to cleave fibrillar collagen, and more controversially there is evidence that #2 is capable of collagenolysis. In MeSH, the current list of collegenases includes #1, #2, #8, #9, and #13. #14 is present in MeSH but not listed as a collegenase, while #18 is absent from MeSH. The main substrates of the gelatinases are type IV collagen and gelatin, and these enzymes are distinguished by the presence of an additional domain inserted into the catalytic domain. This gelatin-binding region is positioned immediately before the zinc binding motif, and forms a separate folding unit which does not disrupt the structure of the catalytic domain. The gelatinases are #2 and #9. The stromelysins display a broad ability to cleave extracellular matrix proteins but are unable to cleave the triple-helical fibrillar collagens. The three canonical members of this group are #3, #10, and #11. All six membrane type MMPs #14, #15, #16, #17, #24, and #25 have a furin cleavage site in the pro-peptide, which is a feature also shared by #11. However, it is becoming increasingly clear that these divisions are somewhat artificial as there are a number of MMPs that do not fit into any of the traditional groups. Genes Gene Name Location Description MMP1 Interstitial collagenase secreted MMP2 Gelatinase-A, 72 kDa gelatinase secreted MMP3 Stromelysin 1 secreted MMP7 Matrilysin, PUMP 1 secreted MMP8 Neutrophil collagenase secreted MMP9 Gelatinase-B, 92 kDa gelatinase secreted MMP10 Stromelysin 2 secreted MMP11 Stromelysin 3 secreted MMP-11 shows more similarity to the MT-MMPs, is convertase-activatable and is secreted therefore usually associated to convertase-activatable MMPs. MMP12 Macrophage metalloelastase secreted MMP13 Collagenase 3 secreted MMP14 MT1-MMP membrane-associated type-I transmembrane MMP MMP15 MT2-MMP membrane-associated type-I transmembrane MMP MMP16 MT3-MMP membrane-associated type-I transmembrane MMP MMP17 MT4-MMP membrane-associated glycosyl phosphatidylinositol-attached MMP18 Collagenase 4, xcol4, xenopus collagenase - No known human orthologue MMP19 RASI-1, occasionally referred to as stromelysin-4 - MMP20 Enamelysin secreted MMP21 X-MMP secreted MMP23A CA-MMP membrane-associated type-II transmembrane cysteine array MMP23B - membrane-associated type-II transmembrane cysteine array MMP24 MT5-MMP membrane-associated type-I transmembrane MMP MMP25 MT6-MMP membrane-associated glycosyl phosphatidylinositol-attached MMP26 Matrilysin-2, endometase - MMP27 MMP-22, C-MMP - MMP28 Epilysin secreted Was discovered in 2001 and given its name due to have been discovered in human keratinocytes. Highly expressed in lung, placenta, salivary glands, heart, uterus, skin. Contains a threonine in place of proline in its cysteine switch PRCGVTD. Function The MMPs play an important role in tissue remodeling associated with various physiological and pathological processes such as morphogenesis, angiogenesis, tissue repair, cirrhosis, arthritis and metastasis. MMP-2 and MMP-9 are thought to be important in metastasis. MMP-1 is thought to be important in rheumatoid and osteo-arthritis. Activation mutual activation of MMPs mutual activation of MMPs All MMPs are synthesized in the latent form Zymogen . They are secreted as proenzymes and require extracellular activation. They can be activated in vitro by many mechanisms including organomercurials, chaotropic agents and other proteases. Inhibitors The MMPs are inhibited by specific endogenous tissue inhibitor of metalloproteinases TIMPs, which comprise a family of four protease inhibitors: TIMP-1, TIMP-2, TIMP-3 and TIMP-4. Synthetic inhibitors generally contain a chelating group which binds the catalytic zinc atom at the MMP active site tightly. Common chelating groups include hydroxamates, carboxylates, thiols, and phosphinyls. Hydroxymates are particularly potent inhibitors of MMPs and other zinc-dependent enzymes, due to their bidentate chelation of the zinc atom. Other substitutents of these inhibitors are usually designed to interact with various binding pockets on the MMP of interest, making the inhibitor more or less specific for given MMPs. Pharmacology Doxycycline, at subantimicrobial doses, inhibits MMP activity, and has been used in various experimental systems for this purpose. It is used clinically for the treatment of periodontal disease and is the only MMP inhibitor which is widely available clinically. It is sold under the trade name Periostat by the company CollaGenex. Minocycline, another tetracycline antibiotic, has also been shown to inhibit MMP activity. A number of rationally designed MMP inhibitors have shown some promise in the treatment of pathologies which MMPs are suspected to be involved in see above. However, most of these, such as marimastat BB-2516, a broad spectrum MMP inhibitor, and trocade Ro 32-3555, an MMP-1 selective inhibitor, have performed poorly in clinical trials. The failure of Marimastat was partially responsible for the folding of British Biotech, which developed it. The failure of these drugs has been largely due to toxicity particularly musculo-skeletal toxicity in the case of broad spectrum inhibitors and failure to show expected results in the case of trocade, promising results in rabbit arthritis models were not replicated in human trials. The reasons behind the largely disappointing clinical results of MMP inhibitors is unclear, especially in light of their activity in animal models. References ^ Remacle AG, Rozanov DV, Fugere M, Day R, Strongin AY. Furin regulates the intracellular activation and the uptake rate of cell surface-associated MT1-MMP. Oncogene. September 14, 2006;2541:5648-55 ^ Gross J, Lapiere C 1962. Collagenolytic activity in amphibian tissues: a tissue culture assay. Proc Natl Acad Sci U S A 48: 1014-22. doi:10.1073/pnas.48.6.1014. PMID 13902219. ^ Eisen A, Jeffrey J, Gross J 1968. Human skin collagenase. Isolation and mechanism of attack on the collagen molecule. Biochim Biophys Acta 151 3: 637-45. PMID 4967132. ^ Harper E, Bloch K, Gross J 1971. The zymogen of tadpole collagenase. Biochemistry 10 16: 3035-41. doi:10.1021/bi00792a008. PMID 4331330. ^ Van Wart H, Birkedal-Hansen H 1990. The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc Natl Acad Sci U S A 87 14: 5578-82. doi:10.1073/pnas.87.14.5578. PMID 2164689. ^ Pei D, Kang T, Qi H 2000. Cysteine array matrix metalloproteinase CA-MMP/MMP-23 is a type II transmembrane matrix metalloproteinase regulated by a single cleavage for both secretion and activation. J Biol Chem 275 43: 33988-97. doi:10.1074/jbc.M006493200. PMID 10945999. ^ Trexler M, Briknarová K, Gehrmann M, Llinás M, Patthy L 2003. Peptide ligands for the fibronectin type II modules of matrix metalloproteinase 2 MMP-2. J Biol Chem 278 14: 12241-6. doi:10.1074/jbc.M210116200. PMID 12486137. ^ Browner MF, Smith WW, Castelhano AL 1995. Matrilysin-inhibitor complexes: common themes among metalloproteases. Biochemistry 34 20: 6602-10. doi:10.1021/bi00020a004. PMID 7756291. ^ Kester WR, Matthews BW 1977. Crystallographic study of the binding of dipeptide inhibitors to thermolysin: implications for the mechanism of catalysis. Biochemistry 16 11: 2506-16. doi:10.1021/bi00630a030. PMID 861218. ^ Manzetti S, McCulloch DR, Herington AC, van der Spoel D 2003. Modeling of enzyme-substrate complexes for the metalloproteases MMP-3, ADAM-9 and ADAM-10. J. Comput. Aided Mol. Des. 17 9: 551-65. doi:10.1023/B:JCAM.0000005765.13637.38. PMID 14713188. External links The Matrix Metalloproteinase Protein Extracellular proteolysis at fibrinolysis.org Currently identified substrates for mammalian MMPs at clip.ubc.ca MeSH Matrix+metalloproteinases v d e Proteases: metalloendopeptidases EC 3.4.24 ADAM proteins Alpha secretases ADAM9 · ADAM10 · ADAM17 · ADAM19 · ADAM2 · ADAM7 · ADAM8 · ADAM11 · ADAM12 · ADAM15 · ADAM18 · ADAM22 · ADAM23 · ADAM28 · ADAM33 · ADAMTS1 · ADAMTS2 · ADAMTS3 · ADAMTS4 · ADAMTS5 · ADAMTS8 · ADAMTS9 · ADAMTS10 · ADAMTS12 · ADAMTS13 Matrix metalloproteinase Collagenase · Gelatinase Other Neprilysin · Procollagen peptidase · Thermolysin · Pregnancy-associated plasma protein A · Bone morphogenetic protein 1 · Insulysin · Lysostaphin · Insulin degrading enzyme Retrieved from http://en..org/wiki/Matrix_metalloproteinase Categories: EC 3.4.24 | Metalloproteins | Zinc compounds Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page Languages Français 日本語 Português This page was last modified on 25 August 2008, at 21:12
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