2006
DOI: 10.1074/jbc.m606004200
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The Roles of Substrate Thermal Stability and P2 and P1′ Subsite Identity on Matrix Metalloproteinase Triple-helical Peptidase Activity and Collagen Specificity

Abstract: The hydrolysis of collagen (collagenolysis) is one of the committed steps in extracellular matrix turnover. Within the matrix metalloproteinase (MMP) family distinct preferences for collagen types are seen. The substrate determinants that may guide these specificities are unknown. In this study, we have utilized 12 triple-helical substrates in combination with 10 MMPs to better define the contributions of substrate sequence and thermal stability toward triple helicase activity and collagen specificity. In gene… Show more

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Cited by 89 publications
(144 citation statements)
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“…Elastins and collagens should spill out of the cleft. Consistent with this, the triple helical peptidase activity of MMP-1, -8, and -12 involves the V-B loop preceding the active-site helix B (33,(45)(46)(47). A triple helical peptide substrate derived from collagen V contacts not only this exosite but also appears to cover other sites in loops and atop the ␤-sheet even more remote from the active site cleft of MMP-12 (33).…”
mentioning
confidence: 67%
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“…Elastins and collagens should spill out of the cleft. Consistent with this, the triple helical peptidase activity of MMP-1, -8, and -12 involves the V-B loop preceding the active-site helix B (33,(45)(46)(47). A triple helical peptide substrate derived from collagen V contacts not only this exosite but also appears to cover other sites in loops and atop the ␤-sheet even more remote from the active site cleft of MMP-12 (33).…”
mentioning
confidence: 67%
“…The lesions' impact on specific activities for substrates from type IV and V collagen raises an important question: Do the corresponding positions in orthodox collagenolytic MMPs modulate their turnover of collagen triple helices? This possibility is suggested by MMP-1 and -8 relying on the V-B loop (45)(46)(47). The exosite of Fig.…”
Section: Of Ref 33)mentioning
confidence: 99%
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“…In addition to the impact of ancillary domains in binding collagen, cleavage of this complex substrate is fundamentally different from hydrolysis of linear peptide/protein substrates by MMPs. This distinction is illustrated by work with triple helical peptides that model collagen structure (45)(46)(47). It will be interesting to know how the SDPs identified here contribute to this multistep process of collagen cleavage, which is unique to only a few MMPs.…”
Section: Discussionmentioning
confidence: 99%
“…However, several members of the matrix metalloproteinase (MMP) 2 subfamily of zinc-dependent endopeptidases catalyze the hydrolysis of triple helices (5). Although highly homologous, MMPs have distinct preferences among collagenous substrates (5,8). MMP-1, MMP-8, MMP-13, and MMP-14/ membrane-type 1 MMP (MT1-MMP) are collagenases that hydrolyze the triple helix of fibrillar type I-III collagens with varying efficiencies at a single GlyϳIle/Leu site.…”
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confidence: 99%