Interstitial Collagen Catabolism
2013; Elsevier BV; Volume: 288; Issue: 13 Linguagem: Inglês
10.1074/jbc.r113.451211
ISSN1083-351X
Autores Tópico(s)Protease and Inhibitor Mechanisms
ResumoInterstitial collagen mechanical and biological properties are altered by proteases that catalyze the hydrolysis of the collagen triple-helical structure. Collagenolysis is critical in development and homeostasis but also contributes to numerous pathologies. Mammalian collagenolytic enzymes include matrix metalloproteinases, cathepsin K, and neutrophil elastase, and a variety of invertebrates and pathogens possess collagenolytic enzymes. Components of the mechanism of action for the collagenolytic enzyme MMP-1 have been defined experimentally, and insights into other collagenolytic mechanisms have been provided. Ancillary biomolecules may modulate the action of collagenolytic enzymes. Interstitial collagen mechanical and biological properties are altered by proteases that catalyze the hydrolysis of the collagen triple-helical structure. Collagenolysis is critical in development and homeostasis but also contributes to numerous pathologies. Mammalian collagenolytic enzymes include matrix metalloproteinases, cathepsin K, and neutrophil elastase, and a variety of invertebrates and pathogens possess collagenolytic enzymes. Components of the mechanism of action for the collagenolytic enzyme MMP-1 have been defined experimentally, and insights into other collagenolytic mechanisms have been provided. Ancillary biomolecules may modulate the action of collagenolytic enzymes. Collagens are composed of three α chains of primarily repeating Gly-Xaa-Yaa triplets, which induce each α chain to adopt a left-handed poly-Pro II helix. Three chains then intertwine, staggered by one residue and coiled, to form a right-handed triple helix. Triple helices assemble to form semicrystalline aggregates referred to as fibrils, and bundles of fibrils form fibers. The proteolysis of interstitial collagen (types I–III) is integral for numerous physiological functions, including morphogenesis, tissue remodeling, and wound healing, and has been recognized as a contributing factor to multiple pathologies, including tumor cell spreading (metastasis), arthritis, glomerulonephritis, periodontal disease, tissue ulcerations, cardiovascular disease, and neurodegenerative diseases. Identifying proteases capable of processing triple helices provides a starting point for defining the roles of collagen catabolism in health and disease. Members of the matrix metalloproteinase (MMP) 2The abbreviations used are: MMPmatrix metalloproteinaseMTmembrane-typeTHPtriple-helical peptideCATcatalyticHPXhemopexin-likeMOmaximum occurrenceCBDcollagen-binding domain. family of zinc-dependent endopeptidases possess collagenolytic activity (1Lauer-Fields J.L. Juska D. Fields G.B. Matrix metalloproteinases and collagen catabolism.Biopolymers. 2002; 66: 19-32Crossref PubMed Scopus (181) Google Scholar). Interstitial collagens are hydrolyzed by the “classic” collagenases, MMP-1, MMP-8, and MMP-13 (Fig. 1), into 1/4 and 3/4 length fragments (Table 1) (1Lauer-Fields J.L. Juska D. Fields G.B. Matrix metalloproteinases and collagen catabolism.Biopolymers. 2002; 66: 19-32Crossref PubMed Scopus (181) Google Scholar, 2Fields G.B. A model for interstitial collagen catabolism by mammalian collagenases.J. Theor. Biol. 1991; 153: 585-602Crossref PubMed Google Scholar). MMP-2 (Fig. 1) cleaves type I collagen (3Barrett A.J. Rawlings N.D. Woessner J.F. Handbook of Proteolytic Enzymes.2nd Ed. Elsevier Academic Press, Amsterdam2004Google Scholar), although how robust the collagenolytic activity is has been brought into question (4Collier I.E. Legant W. Marmer B. Lubman O. Saffarian S. Wakatsuki T. Elson E. Goldberg G.I. Diffusion of MMPs on the surface of collagen fibrils: the mobile cell surface-collagen substratum interface.PLoS ONE. 2011; 6: e24029Crossref PubMed Scopus (61) Google Scholar). MMP-9 (Fig. 1) cleaves type I and III collagens (5Bigg H.F. Rowan A.D. Barker M.D. Cawston T.E. Activity of matrix metalloproteinase-9 against native collagen types I and III.FEBS J. 2007; 274: 1246-1255Crossref PubMed Scopus (92) Google Scholar). Hydrolysis of type I collagen was monitored at 37 °C, at which some denatured triple helices might exist. For MMP-2 and MMP-9, the cleavage site is the same as for the classic collagenases (Table 1).TABLE 1Representative protease cleavage sites within interstitial collagen triple-helical domainsEnzymeCollagen chainSequenceaNumbering begins at the N terminus of the triple-helical region of each collagen.MMP-1/2/8/9/12/13 and MT1-MMPα1(I)Pro-Gln-Gly775∼Ile776-Ala-GlyMMP-1/2/8/9/12/13 and MT1-MMPα2(I)Pro-Gln-Gly775∼Leu776-Leu-GlyMMP-1/8/13 and MT1-MMPα1(II)Pro-Gln-Gly775∼Leu776-Ala-GlyMMP-1/8/9/12/13, MT1-MMP, and MT3-MMPα1(III)Pro-Leu-Gly775∼Ile776-Ala-GlyCathepsin Kα1(I)Gly-Pro-Arg9∼Gly10-Leu-ProCathepsin Kα1(I)Gly-Pro-Gln21∼Gly22-Phe-GlnCathepsin Kα1(I)Gly-Leu-Asp96∼Gly97-Ala-LysCathepsin Kα1(I)Gly-Pro-Gln189∼Gly190-Val-ArgCathepsin Kα1(I)Gly-Pro-Ser810∼Gly811-Ala-SerCathepsin Kα2(I)Gly-Pro-Arg9∼Gly10-Pro-ProCathepsin Kα2(I)Gly-Pro-Gln21∼Gly22-Phe-GlnCathepsin Kα2(I)Gly-Leu-Lys99∼Gly100-Pro-GlnCathepsin Kα2(I)Gly-Ala-Arg144∼Gly145-Ser-AspCathepsin Kα2(I)Pro-Pro-Gly814∼Ala815-Arg-GlyCathepsin Kα1(II)Lys-Pro-Gly61∼Lys62-Ser-GlyElastaseα1(III)Ala-Gly-Ile779∼Thr780-Gly-ArgCrab collagenase 1α1(I)Ala-Gly-Gln779∼Arg780-Gly-ValCrab collagenase 1α1(I)Gly-Gln-Arg780∼Gly781-Val-ValCrab collagenase 1α1(I)Gly-Glu-Arg792∼Gly793-Phe-HypCrab collagenase 1α1(I)Arg-Gly-Leu587∼Thr588-Gly-ProCrab collagenase 1α2(I)Gly-Phe-Leu783∼Gly784-Leu-ProCardosin Aα2(I)Pro-Gly-Phe464∼Asn465-Gly-LeuKumamolisin-As/ScpAα1(I)Gly-Pro-Lys108∼Gly109-Glu-HypKumamolisin-As/ScpAα1(I)Gly-Pro-Arg183∼Gly184-Ser-GluKumamolisin-As/ScpAα1(I)Gly-Ala-Arg396∼Gly397-Gln-AlaKumamolisin-As/ScpAα1(I)Gly-Asp-Ala489∼Gly490-Ala-HypKumamolisin-As/ScpAα2(I)Gly-Pro-Arg42∼Gly43-Pro-AlaGP2α1(I)Gly-Pro-Ala285∼Gly286-Glu-GluGP2α1(I)Gly-Ala-Arg498∼Gly499-Glu-ArgGP2α1(I)Gly-Pro-Ser711∼Gly712-Asn-AlaGP2α2(I)Gly-Pro-Ser285∼Gly286-Glu-GluGP2α2(I)Gly-Ala-Arg498∼Gly499-Glu-ArgGP2α2(I)Gly-Pro-Ser711∼Gly712-Ile-SerColGα1(II)Gly-Phe-Gln24∼Gly25-Asn-ProColGα1(III)Gly-Glu-Arg69∼Gly70-Leu-HypColHα1(I)Gly-Ala-Arg396∼Gly397-Gln-AlaColHα2(I)Gly-Ala-Arg396∼Gly397-Glu-ProColHα1(II)Gly-Phe-Pro405∼Gly406-Pro-LysColHα1(III)Gly-Pro-Arg399∼Gly400-Gln-Hypa Numbering begins at the N terminus of the triple-helical region of each collagen. Open table in a new tab matrix metalloproteinase membrane-type triple-helical peptide catalytic hemopexin-like maximum occurrence collagen-binding domain. Two membrane-type (MT) MMPs (MT-MMPs), MT1-MMP and MT2-MMP, allow invasion-incompetent cells to penetrate type I collagen matrices (6Hotary K. Allen E. Punturieri A. Yana I. Weiss S.J. Regulation of cell invasion and morphogenesis in a three-dimensional type I collagen matrix by membrane-type matrix metalloproteinases 1, 2, and 3.J. Cell Biol. 2000; 149: 1309-1323Crossref PubMed Scopus (507) Google Scholar). MT1-MMP (Fig. 1) processes type I-III collagens at the same site as the classic collagenases (Table 1) (3Barrett A.J. Rawlings N.D. Woessner J.F. Handbook of Proteolytic Enzymes.2nd Ed. Elsevier Academic Press, Amsterdam2004Google Scholar). MT3-MMP also cleaves type III collagen at the classic site (Table 1) (3Barrett A.J. Rawlings N.D. Woessner J.F. Handbook of Proteolytic Enzymes.2nd Ed. Elsevier Academic Press, Amsterdam2004Google Scholar). MT6-MMP was initially reported to have little or no collagenolytic activity (7Kang T. Yi J. Guo A. Wang X. Overall C.M. Jiang W. Elde R. Borregaard N. Pei D. Subcellular distribution and cytokine- and chemokine-regulated secretion of leukolysin/MT6-MMP/MMP-25 in neutrophils.J. Biol. Chem. 2001; 276: 21960-21968Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 8Radichev I.A. Remacle A.G. Shiryaev S.A. Purves A.N. Johnson S.L. Pellecchia M. Strongin A.Y. Biochemical characterization of the cellular glycosylphosphatidylinositol-linked membrane type-6 matrix metalloproteinase.J. Biol. Chem. 2010; 285: 16076-16086Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar) but was subsequently found to cleave type I and II collagens (albeit at 37 °C) (9Starr A.E. Bellac C.L. Dufour A. Goebeler V. Overall C.M. Biochemical characterization and N-terminomics analysis of leukolysin, the membrane-type 6 matrix metalloprotease (MMP25). Chemokine and vimentin cleavages enhance cell migration and macrophage phagocytic activities.J. Biol. Chem. 2012; 287: 13382-13395Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar) and a triple-helical peptide (THP) model of the classic collagenase cleavage site (10Amar, S., Fields, G. B., (2012) Production and characterization of matrix metalloproteinases implicated in multiple sclerosis. in Peptides 2012: Proceedings of the Thirty-Second European Peptide Symposium (Kokotos, G., Constantinou-Kokotou, V., Matsoukas, J., eds) pp. 102–103, European Peptide Society, Athens, GreeceGoogle Scholar). The catalytic (CAT) domain of MMP-12 processes type I and III collagens, where hydrolysis occurs at the classic cleavage site and numerous other sites (11Taddese S. Jung M.C. Ihling C. Heinz A. Neubert R.H.H. Schmelzer C.E.H. MMP-12 catalytic domain recognizes and cleaves at multiple sites in human skin collagen type I and type III.Biochim. Biophys. Acta. 2010; 1804: 731-739Crossref PubMed Scopus (25) Google Scholar). The classic collagenase cleavage site seems to be the most sensitive to MMP-12 (Table 1). Xenopus laevis MMP-18 and chicken MMP-22/MMP-27 cleave type I collagen at the same site as the classic collagenases (3Barrett A.J. Rawlings N.D. Woessner J.F. Handbook of Proteolytic Enzymes.2nd Ed. Elsevier Academic Press, Amsterdam2004Google Scholar). The interstitial collagen triple helix is cleaved by the Cys protease cathepsin K under acidic conditions (optimum pH 5.0). Five distinct sites of cathepsin K hydrolysis type I collagen have been identified, as well as one in type II collagen (Table 1) (12Garnero P. Borel O. Byrjalsen I. Ferreras M. Drake F.H. McQueney M.S. Foged N.T. Delmas P.D. Delaissé J.-M. The collagenolytic activity of cathepsin K is unique among mammalian proteinases.J. Biol. Chem. 1998; 273: 32347-32352Abstract Full Text Full Text PDF PubMed Scopus (536) Google Scholar, 13Kafienah W. Brömme D. Buttle D.J. Croucher L.J. Hollander A.P. Human cathepsin K cleaves native type I and II collagens at the N-terminal end of the triple helix.Biochem. J. 1998; 331: 727-732Crossref PubMed Scopus (295) Google Scholar). An extracellular Ser protease contributes to collagenolysis by temporomandibular joint fibroblasts (14Song F. Bergdoll A.S. Windsor L.J. Temporomandibular joint synovial fibroblasts mediate serine proteinase-dependent type I collagen degradation.Biochim. Biophys. Acta. 2006; 1760: 1521-1528Crossref PubMed Scopus (3) Google Scholar). Several Ser proteases possess interstitial collagenolytic activity, including human neutrophil elastase, Uca pugilator (fiddler crab) collagenase 1, Hypoderma lineatum (insect) collagenase, Penaeus vanameii (shrimp) chymotrypsin, and Pseudoalteromonas sp. SM9913 deseasin MCP-01 (3Barrett A.J. Rawlings N.D. Woessner J.F. Handbook of Proteolytic Enzymes.2nd Ed. Elsevier Academic Press, Amsterdam2004Google Scholar, 15Mainardi C.L. Hasty D.L. Seyer J.M. Kang A.H. Specific cleavage of human type III collagen human polymorphonuclear leukocyte elastase.J. Biol. Chem. 1980; 255: 12006-12010Abstract Full Text PDF PubMed Google Scholar, 16Lecroisey A. Gilles A.-M. De Wolf A. Keil B. Complete amino acid sequence of the collagenase from the insect Hypoderma lineatum.J. Biol. Chem. 1987; 262: 7546-7551Abstract Full Text PDF PubMed Google Scholar, 17Tsu C.A. Perona J.J. Schellenberger V. Turck C.W. Craik C.S. The substrate specificity of Uca pugilator collagenolytic serine protease 1 correlates with the bovine type I collagen cleavage sites.J. Biol. Chem. 1994; 269: 19565-19572Abstract Full Text PDF PubMed Google Scholar, 18Wang Y.-K. Zhao G.-Y. Li Y. Chen X.-L. Xie B.-B. Su H.-N. Lv Y.-H. He H.-L. Liu H. Hu J. Zhou B.-C. Zhang Y.-Z. Mechanistic insight into the function of the C-terminal PKD domain of the collagenolytic serine protease deseasin MCP-01 from deep sea Pseudoalteromonas sp. SM9913.J. Biol. Chem. 2010; 285: 14285-14291Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar). However, neutrophil elastase is ineffective toward fibrillar type III collagen (19Birkedal-Hansen H. Taylor R.E. Bhown A.S. Katz J. Lin H.-Y. Wells B.R. Cleavage of bovine skin type III collagen by proteolytic enzymes.J. Biol. Chem. 1985; 260: 16411-16417Abstract Full Text PDF PubMed Google Scholar). For a number of collagenolytic Ser proteases, the site of collagen cleavage is close to the site of MMP action (Table 1). Although initially reported as being collagenolytic, the Ser proteases fibroblast activation protein/separase and trypsin-2 do not cleave interstitial collagens within their triple helices (20Christiansen V.J. Jackson K.W. Lee K.N. McKee P.A. Effect of fibroblast activation protein and α2-antiplasmin cleaving enzyme on collagen types I, III, and IV.Arch. Biochem. Biophys. 2007; 457: 177-186Crossref PubMed Scopus (84) Google Scholar). 3L. S. Mirigian, E. Makareeva, H. Koistinen, O. Itkonen, T. Sorsa, U.-H. Stenman, T. Salo, and S. Leikin, manuscript submitted for publication. Additional interstitial collagenases include several that act under acidic conditions, such as Cynara cardunculus Asp protease cardosin A (22Duarte A.S. Pereira A.O. Cabrita A.M.S. Moir A.J.G. Pires E.M.V. Barros M.M.T. The characterisation of collagenolytic activity of cardosin A demonstrates its potential application for extracellular matrix degradative processes.Curr. Drug Discov. Technol. 2005; 2: 37-44Crossref PubMed Scopus (12) Google Scholar) and Alicyclobacillus sendaiensis Ser-carboxyl protease kumamolisin-As/ScpA (23Tsuruoka N. Nakayama T. Ashida M. Hemmi H. Nakao M. Minakata H. Oyama H. Oda K. Nishino T. Collagenolytic serine-carboxyl proteinase from Alicyclobacillus sendaiensis strain NTAP-1: purification, characterization, gene cloning, and heterologous expression.Appl. Environ. Microbiol. 2003; 69: 162-169Crossref PubMed Scopus (55) Google Scholar), as well as the Cys proteases ginger (Zingiber officinale) GP2 and GP3 (24Kim M. Hamilton S.E. Guddat L.W. Overall C.M. Plant collagenase: unique collagenolytic activity of cysteine proteases from ginger.Biochim. Biophys. Acta. 2007; 1770: 1627-1635Crossref PubMed Scopus (57) Google Scholar) and Fasciola hepatica FhCL2 and FhCL3 (25Robinson M.W. Corvo I. Jones P.M. George A.M. Padula M.P. To J. Cancela M. Rinaldi G. Tort J.F. Roche L. Dalton J.P. Collagenolytic activities of the major secreted cathepsin L peptidases involved in the virulence of the helminth pathogen, Fasciola hepatica.PLoS Negl. Trop. Dis. 2011; 5: e1012Crossref PubMed Scopus (60) Google Scholar). GP2 hydrolyzes type I collagen at three distinct sites (Table 1) (24Kim M. Hamilton S.E. Guddat L.W. Overall C.M. Plant collagenase: unique collagenolytic activity of cysteine proteases from ginger.Biochim. Biophys. Acta. 2007; 1770: 1627-1635Crossref PubMed Scopus (57) Google Scholar). FhCL2 cleaves the α1(I) chain at 43 sites and the α2(I) chain at 26 sites, whereas FhCL3 cleaves the α1(I) chain at 24 sites and the α2(I) chain at 24 sites, with only three sites shared by the two proteases (25Robinson M.W. Corvo I. Jones P.M. George A.M. Padula M.P. To J. Cancela M. Rinaldi G. Tort J.F. Roche L. Dalton J.P. Collagenolytic activities of the major secreted cathepsin L peptidases involved in the virulence of the helminth pathogen, Fasciola hepatica.PLoS Negl. Trop. Dis. 2011; 5: e1012Crossref PubMed Scopus (60) Google Scholar). Clostridium histolyticum possesses two zinc proteases with collagenolytic activity: class I (ColG) and class II (ColH) (Fig. 1). ColG cleaves interstitial collagens initially near the N termini, whereas ColH cleaves interstitial collagens near the middle to produce 35- and 62-kDa fragments (Table 1) (26French M.F. Bhown A. Van Wart H.E. Identification of Clostridium histolyticum collagenase hyper-reactive sites in type I, II, and III collagens: lack of correlation with local triple helical stability.J. Protein Chem. 1992; 11: 83-97Crossref PubMed Scopus (61) Google Scholar). Clostridium perfringens produces a collagenase that is highly similar to ColG, whereas Vibrio alginolyticus collagenase is a zinc protease that initially processes collagen at a similar site as collagenolytic MMPs (3Barrett A.J. Rawlings N.D. Woessner J.F. Handbook of Proteolytic Enzymes.2nd Ed. Elsevier Academic Press, Amsterdam2004Google Scholar). There are presently four pathways that have been considered for mammalian collagen catabolism: 1) phagocytosis mediated by the α2β1 integrin, where internalized insoluble collagen is transported to lysosomes and degraded by cathepsins (27Arora P.D. Manolson M.F. Downey G.P. Sodek J. McCulloch C.A. A novel model system for characterization of phagosomal maturation, acidification, and intracellular collagen degradation in fibroblasts.J. Biol. Chem. 2000; 275: 35432-35441Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar); 2) cathepsin K collagenolysis in osteoclast-mediated bone resorption (28Costa A.G. Cusano N.E. Silva B.C. Cremers S. Bilezikian J.P. Cathepsin K: its skeletal actions and role as a therapeutic target in osteoporosis.Nat. Rev. Rheumatol. 2011; 7: 447-456Crossref PubMed Scopus (205) Google Scholar); 3) extracellular MMP hydrolysis, followed by gelatinolytic MMPs laterally diffusing on collagen extracellularly, finding “tails” from the cleaved sites, denaturing the triple helix, and further proteolyzing the α chains (29Atkinson S.J. Patterson M.L. Butler M.J. Murphy G. Membrane type 1 matrix metalloproteinase and gelatinase A synergistically degrade type I collagen in a cell model.FEBS Lett. 2001; 491: 222-226Crossref PubMed Scopus (48) Google Scholar, 30Rosenblum G. Van den Steen P.E. Cohen S.R. Bitler A. Brand D.D. Opdenakker G. Sagi I. Direct visualization of protease action on collagen triple helical structure.PLoS ONE. 2010; 5: e11043Crossref PubMed Scopus (60) Google Scholar); and 4) extracellular MMP hydrolysis, followed by the resulting collagen fragments undergoing endocytosis (mediated by urokinase plasminogen activator receptor-associated protein/Endo180 on mesenchymal cells and mannose receptor on macrophages), lysosomal delivery, and cathepsin-catalyzed degradation (31Madsen D.H. Ingvarsen S. Jürgensen H.J. Melander M.C. Kjøller L. Moyer A. Honoré C. Madsen C.A. Garred P. Burgdorf S. Bugge T.H. Behrendt N. Engelholm L.H. The non-phagocytic route of collagen uptake: a distinct degradation pathway.J. Biol. Chem. 2011; 286: 26996-27010Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). Collagen can also be degraded intracellularly by autophagy-mediated lysosomal processes, which may be a form of collagen regulation (32Kim S.I. Na H.-J. Ding Y. Wang Z. Lee S.J. Choi M.E. Autophagy promotes intracellular degradation of type I collagen induced by transforming growth factor (TGF)-β1.J. Biol. Chem. 2012; 287: 11677-11688Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar). In vivo processing of collagen for pathways 1) and 2) above initially involves MMP interaction with fibrils. Hydrolysis of collagen proceeds at the outer edge of the fibril (33Welgus H.G. Jeffrey J.J. Eisen A.Z. Human skin fibroblast collagenase. Assessment of activation energy and deuterium isotope effect with collagenous substrates.J. Biol. Chem. 1981; 256: 9516-9521Abstract Full Text PDF PubMed Google Scholar, 34Perumal S. Antipova O. Orgel J.P.R.O. Collagen fibril architecture, domain organization, and triple-helical conformation govern its proteolysis.Proc. Natl. Acad. Sci. U.S.A. 2008; 105: 2824-2829Crossref PubMed Scopus (265) Google Scholar). MMP-1 is a diffusion-based “burnt bridge” Brownian ratchet capable of biased diffusion on the surface of collagen fibrils, where the bias is driven by proteolysis (35Saffarian S. Collier I.E. Marmer B.L. Elson E.L. Goldberg G. Interstitial collagenase is a Brownian ratchet driven by proteolysis of collagen.Science. 2004; 306: 108-111Crossref PubMed Scopus (153) Google Scholar). Surface-bound MT1-MMP movement is via a similar diffusion mechanism (4Collier I.E. Legant W. Marmer B. Lubman O. Saffarian S. Wakatsuki T. Elson E. Goldberg G.I. Diffusion of MMPs on the surface of collagen fibrils: the mobile cell surface-collagen substratum interface.PLoS ONE. 2011; 6: e24029Crossref PubMed Scopus (61) Google Scholar). While on collagen fibrils, MMP-1 spends ∼90% of its time in one of two distinct pause classes (36Sarkar S.K. Marmer B. Goldberg G. Neuman K.C. Single-molecule tracking of collagenase on native type I collagen fibrils reveals degradation mechanism.Curr. Biol. 2012; 22: 1047-1056Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar). Class I occurs randomly along the fibril, whereas class II occurs periodically at 1.3 and 1.5 μm along the fibril and exhibits multistep escape kinetics (36Sarkar S.K. Marmer B. Goldberg G. Neuman K.C. Single-molecule tracking of collagenase on native type I collagen fibrils reveals degradation mechanism.Curr. Biol. 2012; 22: 1047-1056Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar). Five percent of the class II pauses result in initiation of processive collagen degradation for ∼15 consecutive cleavage events (36Sarkar S.K. Marmer B. Goldberg G. Neuman K.C. Single-molecule tracking of collagenase on native type I collagen fibrils reveals degradation mechanism.Curr. Biol. 2012; 22: 1047-1056Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar). The temperature dependence of the pauses suggests local unfolding, but the low probability of hydrolysis (∼5%) indicates that local unfolding is not sufficient for hydrolysis (36Sarkar S.K. Marmer B. Goldberg G. Neuman K.C. Single-molecule tracking of collagenase on native type I collagen fibrils reveals degradation mechanism.Curr. Biol. 2012; 22: 1047-1056Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar). MMPs bind to multiple sites in collagen (37Sun H.B. Smith Jr., G.N. Hasty K.A. Yokota H. Atomic force microscopy-based detection of binding and cleavage site of matrix metalloproteinase on individual type II collagen helices.Anal. Biochem. 2000; 283: 153-158Crossref PubMed Scopus (35) Google Scholar), but hydrolysis ultimately occurs at a single site (Table 1). Collagen primary structure is not the only basis for discriminatory MMP collagenolytic behavior (1Lauer-Fields J.L. Juska D. Fields G.B. Matrix metalloproteinases and collagen catabolism.Biopolymers. 2002; 66: 19-32Crossref PubMed Scopus (181) Google Scholar). A model of the cleavage sites in interstitial collagens suggested that all of the information necessary for efficient hydrolysis of collagen is contained in a 24-residue stretch (subsites P13–P12′) (2Fields G.B. A model for interstitial collagen catabolism by mammalian collagenases.J. Theor. Biol. 1991; 153: 585-602Crossref PubMed Google Scholar). Cleavage site regions were distinguished by <10% charged residues, being “tightly” triple-helical (high Pro/Hyp content) prior to the cleavage site and being “loosely” triple-helical (low Pro/Hyp content) following the cleavage site (2Fields G.B. A model for interstitial collagen catabolism by mammalian collagenases.J. Theor. Biol. 1991; 153: 585-602Crossref PubMed Google Scholar). Arg residues in the P5′ or P8′ subsite have been proposed to stabilize the triple helix through electrostatic interactions, and these interactions may need to be disrupted for hydrolysis to occur (38Salsas-Escat R. Stultz C.M. Conformational selection and collagenolysis in type III collagen.Proteins. 2010; 78: 325-335Crossref PubMed Scopus (24) Google Scholar). Soluble collagens are thermally unstable at physiological temperatures, slowly melting unless incorporated into fibrils (39Leikina E. Mertts M.V. Kuznetsova N. Leikin S. Type I collagen is thermally unstable at body temperature.Proc. Natl. Acad. Sci. U.S.A. 2002; 99: 1314-1318Crossref PubMed Scopus (448) Google Scholar). This instability may lead to local flexibility/microunfolding that is needed for protease processing of collagen. Molecular dynamics simulations indicate microunfolding of interstitial collagens at the MMP cleavage site (40Stultz C.M. Localized unfolding of collagen explains collagenase cleavage near imino-poor sites.J. Mol. Biol. 2002; 319: 997-1003Crossref PubMed Scopus (76) Google Scholar, 41Ravikumar K.M. Humphrey J.D. Hwang W. Spontaneous unwinding of a labile domain in a collagen triple helix.J. Mech. Mater. Struct. 2007; 2: 999-1010Crossref Scopus (19) Google Scholar, 42Suárez E. Díaz N. Suárez D. Entropic control of the relative stability of triple-helical collagen peptide models.J. Phys. Chem. B. 2008; 112: 15248-15255Crossref PubMed Scopus (17) Google Scholar). Based on enzyme susceptibility, the type I collagen MMP cleavage site undergoes local reversible relaxation (43Ryhänen L. Zaragoza E.J. Uitto J. Conformational stability of type I collagen triple helix: evidence for temporary and local relaxation of the protein conformation using a proteolytic probe.Arch. Biochem. Biophys. 1983; 223: 562-571Crossref PubMed Scopus (50) Google Scholar), whereas the cleavage site in type III collagen has been proposed to be more flexible than the one in type I collagen (19Birkedal-Hansen H. Taylor R.E. Bhown A.S. Katz J. Lin H.-Y. Wells B.R. Cleavage of bovine skin type III collagen by proteolytic enzymes.J. Biol. Chem. 1985; 260: 16411-16417Abstract Full Text PDF PubMed Google Scholar, 44Welgus H.G. Burgeson R.E. Wootton J.A.M. Minor R.R. Fliszar C. Jeffrey J.J. Degradation of monomeric and fibrillar type III collagens by human skin collagenase.J. Biol. Chem. 1985; 260: 1052-1059Abstract Full Text PDF PubMed Google Scholar). Homotrimeric type I collagen (α1(I)3) is much less susceptible to MMP-1 hydrolysis than heterotrimeric type I collagen, and the effect is not due to binding (45Han S. Makareeva E. Kuznetsova N.V. DeRidder A.M. Sutter M.B. Losert W. Phillips C.L. Visse R. Nagase H. Leikin S. Molecular mechanism of type I collagen homotrimer resistance to mammalian collagenases.J. Biol. Chem. 2010; 285: 22276-22281Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar). The homotrimer is more thermally stable than the heterotrimer by ∼2.5 °C and melts 100 times slower (46Miles C.A. Sims T.J. Camacho N.P. Bailey A.J. The role of the α2 chain in the stabilization of the collagen type I heterotrimer: a study of the type I homotrimer in oim mouse tissues.J. Mol. Biol. 2002; 321: 797-805Crossref PubMed Scopus (76) Google Scholar, 47Kuznetsova N.V. McBride Jr., D.J. Leikin S. Changes in thermal stability and microunfolding pattern of collagen helix resulting from the loss of α2(I) chain in osteogenesis imperfecta murine.J. Mol. Biol. 2003; 331: 191-200Crossref PubMed Scopus (54) Google Scholar). The microunfolding patterns of the two collagen subtypes are different (47Kuznetsova N.V. McBride Jr., D.J. Leikin S. Changes in thermal stability and microunfolding pattern of collagen helix resulting from the loss of α2(I) chain in osteogenesis imperfecta murine.J. Mol. Biol. 2003; 331: 191-200Crossref PubMed Scopus (54) Google Scholar). Thus, the difference between MMP-1 activity toward homotrimeric versus heterotrimeric type I collagen is due to local triple-helical unwinding at the cleavage site (45Han S. Makareeva E. Kuznetsova N.V. DeRidder A.M. Sutter M.B. Losert W. Phillips C.L. Visse R. Nagase H. Leikin S. Molecular mechanism of type I collagen homotrimer resistance to mammalian collagenases.J. Biol. Chem. 2010; 285: 22276-22281Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar). The α2(I) chain also increases hydrophobicity compared with the α1(I) chain, driving out structured water and facilitating hydrolysis (46Miles C.A. Sims T.J. Camacho N.P. Bailey A.J. The role of the α2 chain in the stabilization of the collagen type I heterotrimer: a study of the type I homotrimer in oim mouse tissues.J. Mol. Biol. 2002; 321: 797-805Crossref PubMed Scopus (76) Google Scholar). Homotrimeric type I collagen is produced by a variety of tumor cells and enhances tumor cell proliferation and migration compared with heterotrimeric type I collagen (48Makareeva E. Han S. Vera J.C. Sackett D.L. Holmbeck K. Phillips C.L. Visse R. Nagase H. Leikin S. Carcinomas contain a matrix metalloproteinase-resistant isoform of type I collagen exerting selective support to invasion.Cancer Res. 2010; 70: 4366-4374Crossref PubMed Scopus (78) Google Scholar). The Ile residue in one of the three chains at the site of MMP hydrolysis has a distinct chemical shift, a higher J coupling value, increased dynamics, and decreased local stability (49Xiao J. Addabbo R.M. Lauer J.L. Fields G.B. Baum J. Local conformation and dynamics of isoleucine in the collagenase cleavage site provide a recognition signal for matrix metalloproteinases.J. Biol. Chem. 2010; 285: 34181-34190Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar). This suggests that a single locally dynamic chain, rather than a labile region with three comparably dynamic chains, is a determining factor for collagen to be cleaved by MMPs (49Xiao J. Addabbo R.M. Lauer J.L. Fields G.B. Baum J. Local conformation and dynamics of isoleucine in the collagenase cleavage site provide a recognition signal for matrix metalloproteinases.J. Biol. Chem. 2010; 285: 34181-34190Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar). Also, a Pro residue at the P3 subsite influences the P1′ subsite Ile residue, enhancing its accessibility to collagenolytic MMPs (49Xiao J. Addabbo R.M. Lauer J.L. Fields G.B. Baum
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