Matrix metalloproteinases (MMPs), previously referred to as matrixins because of their role in degradation of the extracellular matrix (ECM), are zinc and calcium dependent proteases belonging to the metzincin family. They contain a characteristic zinc-binding motif HEXXHXXGXXH (Stocker & Bode 1995) and a conserved Methionine which forms a Met-turn. Humans have 24 MMP genes giving rise to 23 MMP proteins, as MMP23 is encoded by two identical genes. All MMPs contain an N-terminal secretory signal peptide and a prodomain with a conserved PRCGXPD motif that in the inactive enzyme is localized with the catalytic site, the cysteine acting as a fourth unpaired ligand for the catalytic zinc atom. Activation involves delocalization of the domain containing this cysteine by a conformational change or proteolytic cleavage, a mechanism referred to as the cysteine-switch (Van Wart & Birkedal-Hansen 1990). Most MMPs are secreted but the membrane type MT-MMPs are membrane anchored and some MMPs may act on intracellular proteins. Various domains determine substrate specificity, cell localization and activation (Hadler-Olsen et al. 2011). MMPs are regulated by transcription, cellular location (most are not activated until secreted), activating proteinases that can be other MMPs, and by metalloproteinase inhibitors such as the tissue inhibitors of metalloproteinases (TIMPs). MMPs are best known for their role in the degradation and removal of ECM molecules. In addition, cleavage of the ECM and other cell surface molecules can release ECM-bound growth factors, and a number of non-ECM proteins are substrates of MMPs (Nagase et al. 2006). MMPs can be divided into subgroups based on domain structure and substrate specificity but it is clear that these are somewhat artificial, many MMPs belong to more than one functional group (Vise & Nagase 2003, Somerville et al. 2003).
Gonzalez EM, Reed CC, Bix G, Fu J, Zhang Y, Gopalakrishnan B, Greenspan DS, Iozzo RV.; ''BMP-1/Tolloid-like metalloproteases process endorepellin, the angiostatic C-terminal fragment of perlecan.''; PubMedEurope PMCScholia
Fukai F, Ohtaki M, Fujii N, Yajima H, Ishii T, Nishizawa Y, Miyazaki K, Katayama T.; ''Release of biological activities from quiescent fibronectin by a conformational change and limited proteolysis by matrix metalloproteinases.''; PubMedEurope PMCScholia
Rodríguez D, Morrison CJ, Overall CM.; ''Matrix metalloproteinases: what do they not do? New substrates and biological roles identified by murine models and proteomics.''; PubMedEurope PMCScholia
Agnihotri R, Crawford HC, Haro H, Matrisian LM, Havrda MC, Liaw L.; ''Osteopontin, a novel substrate for matrix metalloproteinase-3 (stromelysin-1) and matrix metalloproteinase-7 (matrilysin).''; PubMedEurope PMCScholia
Truebestein L, Tennstaedt A, Mönig T, Krojer T, Canellas F, Kaiser M, Clausen T, Ehrmann M.; ''Substrate-induced remodeling of the active site regulates human HTRA1 activity.''; PubMedEurope PMCScholia
Zack MD, Malfait AM, Skepner AP, Yates MP, Griggs DW, Hall T, Hills RL, Alston JT, Nemirovskiy OV, Radabaugh MR, Leone JW, Arner EC, Tortorella MD.; ''ADAM-8 isolated from human osteoarthritic chondrocytes cleaves fibronectin at Ala(271).''; PubMedEurope PMCScholia
Samanna V, Wei H, Ego-Osuala D, Chellaiah MA.; ''Alpha-V-dependent outside-in signaling is required for the regulation of CD44 surface expression, MMP-2 secretion, and cell migration by osteopontin in human melanoma cells.''; PubMedEurope PMCScholia
Chamberland A, Wang E, Jones AR, Collins-Racie LA, LaVallie ER, Huang Y, Liu L, Morris EA, Flannery CR, Yang Z.; ''Identification of a novel HtrA1-susceptible cleavage site in human aggrecan: evidence for the involvement of HtrA1 in aggrecan proteolysis in vivo.''; PubMedEurope PMCScholia
Strickland DK, Ashcom JD, Williams S, Burgess WH, Migliorini M, Argraves WS.; ''Sequence identity between the alpha 2-macroglobulin receptor and low density lipoprotein receptor-related protein suggests that this molecule is a multifunctional receptor.''; PubMedEurope PMCScholia
Campbell RL, Davies PL.; ''Structure-function relationships in calpains.''; PubMedEurope PMCScholia
Lu P, Takai K, Weaver VM, Werb Z.; ''Extracellular matrix degradation and remodeling in development and disease.''; PubMedEurope PMCScholia
Taleb S, Cancello R, Clément K, Lacasa D.; ''Cathepsin s promotes human preadipocyte differentiation: possible involvement of fibronectin degradation.''; PubMedEurope PMCScholia
Sorimachi H, Hata S, Ono Y.; ''Expanding members and roles of the calpain superfamily and their genetically modified animals.''; PubMedEurope PMCScholia
Cailhier JF, Sirois I, Laplante P, Lepage S, Raymond MA, Brassard N, Prat A, Iozzo RV, Pshezhetsky AV, Hébert MJ.; ''Caspase-3 activation triggers extracellular cathepsin L release and endorepellin proteolysis.''; PubMedEurope PMCScholia
Maretzky T, Reiss K, Ludwig A, Buchholz J, Scholz F, Proksch E, de Strooper B, Hartmann D, Saftig P.; ''ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and beta-catenin translocation.''; PubMedEurope PMCScholia
Croall DE, Ersfeld K.; ''The calpains: modular designs and functional diversity.''; PubMedEurope PMCScholia
Cauwe B, Van den Steen PE, Opdenakker G.; ''The biochemical, biological, and pathological kaleidoscope of cell surface substrates processed by matrix metalloproteinases.''; PubMedEurope PMCScholia
Nakamura H, Fujii Y, Inoki I, Sugimoto K, Tanzawa K, Matsuki H, Miura R, Yamaguchi Y, Okada Y.; ''Brevican is degraded by matrix metalloproteinases and aggrecanase-1 (ADAMTS4) at different sites.''; PubMedEurope PMCScholia
Hindson VJ, Ashworth JL, Rock MJ, Cunliffe S, Shuttleworth CA, Kielty CM.; ''Fibrillin degradation by matrix metalloproteinases: identification of amino- and carboxy-terminal cleavage sites.''; PubMedEurope PMCScholia
Johnson SK, Ramani VC, Hennings L, Haun RS.; ''Kallikrein 7 enhances pancreatic cancer cell invasion by shedding E-cadherin.''; PubMedEurope PMCScholia
Wu BT, Su YH, Tsai MT, Wasserman SM, Topper JN, Yang RB.; ''A novel secreted, cell-surface glycoprotein containing multiple epidermal growth factor-like repeats and one CUB domain is highly expressed in primary osteoblasts and bones.''; PubMedEurope PMCScholia
Udayakumar TS, Chen ML, Bair EL, Von Bredow DC, Cress AE, Nagle RB, Bowden GT.; ''Membrane type-1-matrix metalloproteinase expressed by prostate carcinoma cells cleaves human laminin-5 beta3 chain and induces cell migration.''; PubMedEurope PMCScholia
Shapiro SD, Kobayashi DK, Ley TJ.; ''Cloning and characterization of a unique elastolytic metalloproteinase produced by human alveolar macrophages.''; PubMedEurope PMCScholia
Mimura T, Han KY, Onguchi T, Chang JH, Kim TI, Kojima T, Zhou Z, Azar DT.; ''MT1-MMP-mediated cleavage of decorin in corneal angiogenesis.''; PubMedEurope PMCScholia
Najy AJ, Day KC, Day ML.; ''The ectodomain shedding of E-cadherin by ADAM15 supports ErbB receptor activation.''; PubMedEurope PMCScholia
Vartio T.; ''Characterization of the binding domains in the fragments cleaved by cathepsin G from human plasma fibronectin.''; PubMedEurope PMCScholia
Butler GS, Overall CM.; ''Updated biological roles for matrix metalloproteinases and new "intracellular" substrates revealed by degradomics.''; PubMedEurope PMCScholia
Nakada M, Miyamori H, Kita D, Takahashi T, Yamashita J, Sato H, Miura R, Yamaguchi Y, Okada Y.; ''Human glioblastomas overexpress ADAMTS-5 that degrades brevican.''; PubMedEurope PMCScholia
Shi F, Sottile J.; ''MT1-MMP regulates the turnover and endocytosis of extracellular matrix fibronectin.''; PubMedEurope PMCScholia
Ahmed N, Pansino F, Clyde R, Murthi P, Quinn MA, Rice GE, Agrez MV, Mok S, Baker MS.; ''Overexpression of alpha(v)beta6 integrin in serous epithelial ovarian cancer regulates extracellular matrix degradation via the plasminogen activation cascade.''; PubMedEurope PMCScholia
Kirschner R, Hubmacher D, Iyengar G, Kaur J, Fagotto-Kaufmann C, Brömme D, Bartels R, Reinhardt DP.; ''Classical and neonatal Marfan syndrome mutations in fibrillin-1 cause differential protease susceptibilities and protein function.''; PubMedEurope PMCScholia
Oka C, Tsujimoto R, Kajikawa M, Koshiba-Takeuchi K, Ina J, Yano M, Tsuchiya A, Ueta Y, Soma A, Kanda H, Matsumoto M, Kawaichi M.; ''HtrA1 serine protease inhibits signaling mediated by Tgfbeta family proteins.''; PubMedEurope PMCScholia
Goll DE, Thompson VF, Li H, Wei W, Cong J.; ''The calpain system.''; PubMedEurope PMCScholia
Symowicz J, Adley BP, Gleason KJ, Johnson JJ, Ghosh S, Fishman DA, Hudson LG, Stack MS.; ''Engagement of collagen-binding integrins promotes matrix metalloproteinase-9-dependent E-cadherin ectodomain shedding in ovarian carcinoma cells.''; PubMedEurope PMCScholia
Sorimachi H, Hata S, Ono Y.; ''Calpain chronicle--an enzyme family under multidisciplinary characterization.''; PubMedEurope PMCScholia
Campbell EJ, Silverman EK, Campbell MA.; ''Elastase and cathepsin G of human monocytes. Quantification of cellular content, release in response to stimuli, and heterogeneity in elastase-mediated proteolytic activity.''; PubMedEurope PMCScholia
Knäuper V, Cowell S, Smith B, López-Otin C, O'Shea M, Morris H, Zardi L, Murphy G.; ''The role of the C-terminal domain of human collagenase-3 (MMP-13) in the activation of procollagenase-3, substrate specificity, and tissue inhibitor of metalloproteinase interaction.''; PubMedEurope PMCScholia
Stracke JO, Hutton M, Stewart M, Pendás AM, Smith B, López-Otin C, Murphy G, Knäuper V.; ''Biochemical characterization of the catalytic domain of human matrix metalloproteinase 19. Evidence for a role as a potent basement membrane degrading enzyme.''; PubMedEurope PMCScholia
Guo H, Li R, Zucker S, Toole BP.; ''EMMPRIN (CD147), an inducer of matrix metalloproteinase synthesis, also binds interstitial collagenase to the tumor cell surface.''; PubMedEurope PMCScholia
Wu YY, Peck K, Chang YL, Pan SH, Cheng YF, Lin JC, Yang RB, Hong TM, Yang PC.; ''SCUBE3 is an endogenous TGF-β receptor ligand and regulates the epithelial-mesenchymal transition in lung cancer.''; PubMedEurope PMCScholia
Lettau I, Hattermann K, Held-Feindt J, Brauer R, Sedlacek R, Mentlein R.; ''Matrix metalloproteinase-19 is highly expressed in astroglial tumors and promotes invasion of glioma cells.''; PubMedEurope PMCScholia
Murphy G, Cockett MI, Ward RV, Docherty AJ.; ''Matrix metalloproteinase degradation of elastin, type IV collagen and proteoglycan. A quantitative comparison of the activities of 95 kDa and 72 kDa gelatinases, stromelysins-1 and -2 and punctuated metalloproteinase (PUMP).''; PubMedEurope PMCScholia
Ashworth JL, Murphy G, Rock MJ, Sherratt MJ, Shapiro SD, Shuttleworth CA, Kielty CM.; ''Fibrillin degradation by matrix metalloproteinases: implications for connective tissue remodelling.''; PubMedEurope PMCScholia
Imai K, Hiramatsu A, Fukushima D, Pierschbacher MD, Okada Y.; ''Degradation of decorin by matrix metalloproteinases: identification of the cleavage sites, kinetic analyses and transforming growth factor-beta1 release.''; PubMedEurope PMCScholia
Ono Y, Sorimachi H.; ''Calpains: an elaborate proteolytic system.''; PubMedEurope PMCScholia
Hu SI, Carozza M, Klein M, Nantermet P, Luk D, Crowl RM.; ''Human HtrA, an evolutionarily conserved serine protease identified as a differentially expressed gene product in osteoarthritic cartilage.''; PubMedEurope PMCScholia
Toole BP.; ''Hyaluronan and its binding proteins, the hyaladherins.''; PubMedEurope PMCScholia
Li T, Ma G, Cai H, Price DL, Wong PC.; ''Nicastrin is required for assembly of presenilin/gamma-secretase complexes to mediate Notch signaling and for processing and trafficking of beta-amyloid precursor protein in mammals.''; PubMedEurope PMCScholia
d'Ortho MP, Will H, Atkinson S, Butler G, Messent A, Gavrilovic J, Smith B, Timpl R, Zardi L, Murphy G.; ''Membrane-type matrix metalloproteinases 1 and 2 exhibit broad-spectrum proteolytic capacities comparable to many matrix metalloproteinases.''; PubMedEurope PMCScholia
Tío L, Martel-Pelletier J, Pelletier JP, Bishop PN, Roughley P, Farran A, Benito P, Monfort J.; ''Characterization of opticin digestion by proteases involved in osteoarthritis development.''; PubMedEurope PMCScholia
Hadler-Olsen E, Fadnes B, Sylte I, Uhlin-Hansen L, Winberg JO.; ''Regulation of matrix metalloproteinase activity in health and disease.''; PubMedEurope PMCScholia
Whitelock JM, Murdoch AD, Iozzo RV, Underwood PA.; ''The degradation of human endothelial cell-derived perlecan and release of bound basic fibroblast growth factor by stromelysin, collagenase, plasmin, and heparanases.''; PubMedEurope PMCScholia
Shi Y.; ''Mechanisms of caspase activation and inhibition during apoptosis.''; PubMedEurope PMCScholia
Steinhusen U, Weiske J, Badock V, Tauber R, Bommert K, Huber O.; ''Cleavage and shedding of E-cadherin after induction of apoptosis.''; PubMedEurope PMCScholia
Velasco G, Cal S, Quesada V, Sánchez LM, López-Otín C.; ''Matriptase-2, a membrane-bound mosaic serine proteinase predominantly expressed in human liver and showing degrading activity against extracellular matrix proteins.''; PubMedEurope PMCScholia
Gronski TJ, Martin RL, Kobayashi DK, Walsh BC, Holman MC, Huber M, Van Wart HE, Shapiro SD.; ''Hydrolysis of a broad spectrum of extracellular matrix proteins by human macrophage elastase.''; PubMedEurope PMCScholia
The matrix metalloproteinases (MMPs), previously known as matrixins, are classically known to be involved in the turnover of extracellular matrix (ECM) components. However, recent high throughput proteomics analyses have revealed that ~80% of MMP substrates are non-ECM proteins including cytokines, growth factor binding protiens, and receptors. It is now clear that MMPs regulate ECM turnover not only by cleaving ECM components, but also by the regulation of cell signalling, and that some MMPs are beneficial and may be drug anti-targets. Thus, MMPs have important roles in many processes including embryo development, morphogenesis, tissue homeostasis and remodeling. They are implicated in several diseases such as arthritis, periodontitis, glomerulonephritis, atherosclerosis, tissue ulceration, and cancer cell invasion and metastasis. All MMPs are synthesized as preproenzymes. Alternate splice forms are known, leading to nuclear localization of select MMPs. Most are secreted from the cell, or in the case of membrane type (MT) MMPs become plasma membrane associated, as inactive proenzymes. Their subsequent activation is a key regulatory step, with requirements specific to MMP subtype.
Collagen fibril diameter and spatial organisation are dependent on the species, tissue type and stage of development (Parry 1988). The lengths of collagen fibrils in mature tissues are largely unknown but in tendon can be measured in millimetres (Craig et al. 1989). Collagen fibrils isolated from adult bovine corneal stroma had ~350 collagen molecules in transverse section, tapering down to three molecules at the growing tip (Holmes & Kadler 2005).
The classical view of collagenases is that they actively unwind the triple helical chain, a process termed molecular tectonics (Overall 2002, Bode & Maskos 2003), before preferentially cleaving the alpha2 chain followed by the remaining chains (Chung et al. 2004). More recently it has been suggested that collagen fibrils exist in an equilibrium between protected and vulnerable states (Stultz 2002, Nerenberg & Stultz 2008). The prototypical triple-helical structure of collagen does not fit into the active site of collagenase MMPs. In addition the scissile bonds are not solvent-exposed and are therefore inaccessible to the collagenase active site (Chung et al. 2004, Stultz 2002). It was realized that collagen must locally unfold into non-triple helical regions to allow collagenolysis. Observations using circular dichroism and differential scanning calorimetry confirm that there is considerable heterogeneity along collagen fibres (Makareeva et al. 2008) allowing access for MMPs at physiological temperatures (Salsas-Escat et al. 2010).
Collagen fibrils with cut chains are unstable and accessible to proteinases that cannot cleave intact collagen strands (Woessner & Nagase 2000, Somerville et al. 2003). Continued degradation leads to the formation of gelatin (Lovejoy et al. 1999). Degradation of collagen types other than I-III is less well characterized but believed to occur in a similar manner.
Metalloproteinases (MMPs) play a major part in the degradation of several extracellular macromolecules including collagens. MMP1 (Welgus et al. 1981), MMP8 (Hasty et al. 1987), and MMP13 (Knauper et al. 1996), sometimes referred to as collagenases I, II and III respectively, are able to initiate the intrahelical cleavage of the major fibril forming collagens I, II and III at neutral pH, and thus thought to define the rate-limiting step in normal tissue remodeling events. All can cleave additional substrates including other collagen subtypes. Collagenases cut collagen alpha chains at a single conserved Gly-Ile/Leu site approximately 3/4 of the molecule's length from the N-terminus (Fields 1991, Chung et al. 2004). The cleavage site is characterised by the motif G(I/L)(A/L); the G-I/L bond is cleaved. In collagen type I this corresponds to G953-I954 in the Uniprot canonical alpha chain sequences (often given as G775-I776 in literature). It is not clear why only this bond is cleaved, as the motif occurs at several other places in the chain. MMP14, a membrane-associated MMP also known as Membrane-type matrix metalloproteinase 1 (MT-MMP1), is able to cleave collagen types I, II and III (Ohuchi et al. 1997).
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The classical view of collagenases is that they actively unwind the triple helical chain, a process termed molecular tectonics (Overall 2002, Bode & Maskos 2003), before preferentially cleaving the alpha2 chain followed by the remaining chains (Chung et al. 2004). More recently it has been suggested that collagen fibrils exist in an equilibrium between protected and vulnerable states (Stultz 2002, Nerenberg & Stultz 2008). The prototypical triple-helical structure of collagen does not fit into the active site of collagenase MMPs. In addition the scissile bonds are not solvent-exposed and are therefore inaccessible to the collagenase active site (Chung et al. 2004, Stultz 2002). It was realized that collagen must locally unfold into non-triple helical regions to allow collagenolysis. Observations using circular dichroism and differential scanning calorimetry confirm that there is considerable heterogeneity along collagen fibres (Makareeva et al. 2008) allowing access for MMPs at physiological temperatures (Salsas-Escat et al. 2010).
Collagen fibrils with cut chains are unstable and accessible to proteinases that cannot cleave intact collagen strands (Woessner & Nagase 2000, Somerville et al. 2003). Continued degradation leads to the formation of gelatin (Lovejoy et al. 1999). Degradation of collagen types other than I-III is less well characterized but believed to occur in a similar manner.
Metalloproteinases (MMPs) play a major part in the degradation of several extracellular macromolecules including collagens. MMP1 (Welgus et al. 1981), MMP8 (Hasty et al. 1987), and MMP13 (Knauper et al. 1996), sometimes referred to as collagenases I, II and III respectively, are able to initiate the intrahelical cleavage of the major fibril forming collagens I, II and III at neutral pH, and thus thought to define the rate-limiting step in normal tissue remodeling events. All can cleave additional substrates including other collagen subtypes. Collagenases cut collagen alpha chains at a single conserved Gly-Ile/Leu site approximately 3/4 of the molecule's length from the N-terminus (Fields 1991, Chung et al. 2004). The cleavage site is characterised by the motif G(I/L)(A/L); the G-I/L bond is cleaved. In collagen type I this corresponds to G953-I954 in the Uniprot canonical alpha chain sequences (often given as G775-I776 in literature). It is not clear why only this bond is cleaved, as the motif occurs at several other places in the chain. MMP14, a membrane-associated MMP also known as Membrane-type matrix metalloproteinase 1 (MT-MMP1), is able to cleave collagen types I, II and III (Ohuchi et al. 1997).
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