Matrix metalloproteinase 507329 222849509 2008-07-01T12:23:04Z DOI bot 6652755 Citation maintenance. Added: year. You can [[WP:DOI|use this bot]] yourself! Please [[User:DOI_bot/bugs|report any bugs]]. [[Image:MMP14as-kosigrim.gif|right|thumb|250px|Cell surface-associated MT1-MMP (MMP14), [[Green fluorescent protein]] (GFP) fused to the C-term produces a signal on the surface of the cell<ref>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. 2006 Sep 14;25(41):5648-55</ref>]] '''Matrix metalloproteinases''' (MMPs) are [[zinc]]-dependent [[endopeptidase]]s; other family members are [[adamalysin]]s, [[serralysin]]s, and [[astacin]]s. The MMPs belong to a larger family of [[protease]]s 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 [[Receptor (biochemistry)|receptor]]s, the release of [[apoptosis|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]], [[cell migration|migration]] ([[cell adhesion|adhesion]]/dispersion), [[Cellular differentiation|differentiation]], [[angiogenesis]], apoptosis and [[Immune system|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 [[Cofactor (biochemistry)|cofactors]], their ability to degrade extracellular matrix, and their specific evolutionary [[DNA sequence]]. ==History== Initially, MMPs were described by Jerome Gross and Charles Lapiere (1962) who observed enzymatic activity ([[collagen]] triple helix degradation) during tadpole tail metamorphosis.<ref>{{cite journal |author=Gross J, Lapiere C |title=Collagenolytic activity in amphibian tissues: a tissue culture assay |journal=Proc Natl Acad Sci U S A |volume=48 |issue= |pages=1014–22 |year= 1962|pmid=13902219 |doi=10.1073/pnas.48.6.1014}}</ref> Therefore, the enzyme was named interstitial collagenase ([[MMP1|MMP-1]]). Later it was purified from human skin (1968)<ref>{{cite journal |author=Eisen A, Jeffrey J, Gross J |title=Human skin collagenase. Isolation and mechanism of attack on the collagen molecule |journal=Biochim Biophys Acta |volume=151 |issue=3 |pages=637–45 |year=1968 |pmid=4967132}}</ref>, and was recognized to be synthesized as a [[zymogen]].<ref>{{cite journal |author=Harper E, Bloch K, Gross J |title=The zymogen of tadpole collagenase |journal=Biochemistry |volume=10 |issue=16 |pages=3035–41 |year=1971 |pmid=4331330 |doi=10.1021/bi00792a008}}</ref> The "cysteine switch" was described in 1990.<ref>{{cite journal |author=Van Wart H, Birkedal-Hansen H |title=The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family |journal=Proc Natl Acad Sci U S A |volume=87 |issue=14 |pages=5578–82 |year=1990 |pmid=2164689 |doi=10.1073/pnas.87.14.5578}}</ref> ==Structure== The MMPs share a common domain [[Protein structure|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 (biochemistry)|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 protein|transmembrane]] segment in this domain.<ref>{{cite journal |author=Pei D, Kang T, Qi H |title=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 |journal=J Biol Chem |volume=275 |issue=43 |pages=33988–97 |year=2000 |pmid=10945999 |doi=10.1074/jbc.M006493200}}</ref> ===The catalytic domain=== [[X-ray crystallography|X-ray crystallographic]] structures of several MMP catalytic domains have shown that this domain is an oblate sphere measuring 35 x 30 x 30 [[angstrom|Å]] (3.5 x 3 x 3 [[nanometer|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 [[zinc|Zn]]<sup>2+</sup> ion, which is bound by three [[histidine]] residues found in the conserved sequence HExxHxxGxxH. Hence, this sequence is a zinc-binding motif. The [[#The gelatinases|gelatinase]]s, such as [[MMP2|MMP-2]], incorporate [[Fibronectin]] type II modules inserted immediately before in the [[zinc]]-binding motif in the catalytic domain.<ref>{{cite journal |author=Trexler M, Briknarová K, Gehrmann M, Llinás M, Patthy L |title=Peptide ligands for the fibronectin type II modules of matrix metalloproteinase 2 ([[MMP2|MMP-2]]) |journal=J Biol Chem |volume=278 |issue=14 |pages=12241–6 |year=2003 |pmid=12486137 |doi=10.1074/jbc.M210116200}}</ref> ===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 acid]]s long, and has no determinable structure. ===The haemopexin-like C-terminal domain=== The C-terminal domain has structural similarities to the [[blood plasma|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]]. [[#The membrane-bound MMPs|MT-MMPs]] are anchored to the [[plasma membrane]], through this domain and some of these have [[cytoplasm]]ic domains. ===Catalytic mechanism=== There are three catalytic mechanisms published. * In the first mechanism, Browner M.F. and colleagues<ref>{{cite journal |author=Browner MF, Smith WW, Castelhano AL |title=Matrilysin-inhibitor complexes: common themes among metalloproteases |journal=Biochemistry |volume=34 |issue=20 |pages=6602–10 |year=1995 |pmid=7756291|doi=10.1021/bi00020a004}}</ref>proposed the base-catalysis mechanism, carried out by the conserved glutamate residue and the [[zinc|Zn<sup>2+</sup>]] ion. * In the second mechanism, the Matthews-mechanism, Kester and Matthews<ref>{{cite journal |author=Kester WR, Matthews BW |title=Crystallographic study of the binding of dipeptide inhibitors to thermolysin: implications for the mechanism of catalysis |journal=Biochemistry |volume=16 |issue=11 |pages=2506–16 |year=1977 |pmid=861218|doi=10.1021/bi00630a030}}</ref> suggested an interaction between a water molecule and the [[zinc|Zn<sup>2+</sup>]] ion during the [[Acid catalysis|acid-base catalysis]]. * In the third mechanism, the Manzetti-mechanism, Manzetti Sergio and colleagues<ref>{{cite journal |author=Manzetti S, McCulloch DR, Herington AC, van der Spoel D |title=Modeling of enzyme-substrate complexes for the metalloproteases MMP-3, ADAM-9 and ADAM-10 |journal=J. Comput. Aided Mol. Des. |volume=17 |issue=9 |pages=551–65 |year=2003 |pmid=14713188|doi=10.1023/B:JCAM.0000005765.13637.38}}</ref> 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 [[zinc|Zn<sup>2+</sup>]] ion to assume a quasi-penta coordinated state, via its dissociation from it. In this state, the [[zinc|Zn<sup>2+</sup>]] 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 the substrate. ==Classification== The MMPs can be subdivided in different ways. ===Evolutionary=== Use of [[bioinformatics|bioinformatic]] methods to compare the primary sequences of the MMPs suggest the following [[evolution]]ary groupings of the MMPs: * MMP-19 * MMPs 11, [[MMP14|14]], 15, 16 and 17 * [[MMP2|MMP-2]] and [[MMP9|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 specificity|substrate specificities]] of the [[enzyme]]s. ===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 [[collagenase]]s are capable of degrading triple-helical fibrillar [[collagen]]s into distinctive 3/4 and 1/4 fragments. These [[collagen]]s are the major components of [[bone]] and [[cartilage]], and MMPs are the only known [[mammal]]ian [[enzyme]]s 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 [[gelatinase]]s are [[collagen|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]] [[protein]]s but are unable to cleave the triple-helical fibrillar [[collagen]]s. The three canonical members of this group are #3, #10, and #11. * All six membrane type MMPs ([[MMP14|#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=== {| class="wikitable" class="sortable wikitable" | '''Gene''' || '''Name''' || '''Location''' || '''Description''' |- | [[MMP1]] || Interstitial collagenase || secreted || |- | [[MMP2]] || Gelatinase-A, 72 [[kilodalton|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 |- | {{Gene|MMP16}} || MT3-MMP || membrane-associated || type-I transmembrane MMP |- | {{Gene|MMP17}} || MT4-MMP || membrane-associated || [[GPI anchor|glycosyl phosphatidylinositol]]-attached |- | ''MMP18'' || Collagenase 4, xcol4, [[xenopus]] collagenase || - || No known human [[orthologue]] |- | {{Gene|MMP19}} || RASI-1, occasionally referred to as stromelysin-4 || - || |- | {{Gene|MMP20}} || Enamelysin || secreted || |- | {{Gene|MMP21}} || X-MMP || secreted || |- | {{Gene|MMP23A}} || CA-MMP || membrane-associated || type-II transmembrane cysteine array |- | {{Gene|MMP23B}} || - || membrane-associated || type-II transmembrane cysteine array |- | {{Gene|MMP24}} || MT5-MMP || membrane-associated || type-I transmembrane MMP |- | {{Gene|MMP25}} || MT6-MMP || membrane-associated || [[GPI anchor|glycosyl phosphatidylinositol]]-attached |- | {{Gene|MMP26}} || Matrilysin-2, endometase || - || |- | {{Gene|MMP27}} || MMP-22, C-MMP || - || |- | {{Gene|MMP28}} || Epilysin || secreted || Was discovered in 2001 and given its name due to have been discovered in human [[keratinocyte]]s. Highly expressed in [[lung]], [[placenta]], [[salivary gland]]s, [[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]]. [[MMP2|MMP-2]] and [[MMP9|MMP-9]] are thought to be important in metastasis. [[MMP1|MMP-1]] is thought to be important in rheumatoid and osteo-arthritis. ==Activation== [[Image:Mutual_MMP_activation.svg|thumb|mutual activation of MMPs|right]] 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 inhibitor]]s: TIMP-1, TIMP-2, TIMP-3 and TIMP-4. Synthetic inhibitors generally contain a [[chelation|chelating group]] which binds the catalytic [[zinc]] atom at the MMP [[active site]] tightly. Common chelating groups include [[hydroxamate]]s, [[carboxylic acid|carboxylates]], [[thiol]]s, and [[phosphinic acid|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 [[MMP1|MMP-1]] selective inhibitor, have performed poorly in [[clinical trial]]s. 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 model]]s. ==References== <div class="references-2column"> <references/> </div> ==External links== * [http://macromoleculeinsights.com/mmp.php The Matrix Metalloproteinase Protein] * [http://www.fibrinolysis.org/NewFiles/Proteins.html Extracellular proteolysis at fibrinolysis.org] * [http://www.clip.ubc.ca/mmp_timp_folder/mmp_substrates.shtm Currently identified substrates for mammalian MMPs at clip.ubc.ca] * {{MeshName|Matrix+metalloproteinases}} {{Metalloproteinases}} [[Category:EC 3.4.24|*]] [[Category:Metalloproteins]] [[Category:Zinc compounds]] [[fr:Métalloprotéinase matricielle]] [[ja:マトリックスメタロプロテアーゼ]] [[pt:Metaloproteinase matriz]]