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Length-dependent proteolytic cleavage of short oligopeptides catalyzed by matrix metalloprotease-9.

ABSTRACT: Matrix metalloproteinases (MMPs), as the enzymes to degrade extracellular matrix proteins, play a major role on cell behaviors. Among them, MMP-9 usually catalyzes the degradation of proteins with the dominant cleavage at G/L site. Recent high-throughput screening suggests that S/L is a new major site for the cleavage when the substrates of MMP-9 are oligopeptides. Here we examine the cleavage sites of the N-terminal substituted short oligopeptides as the substrates of MMP-9. As the first example of such study of N-substituted small peptides, our results suggest that the substitute group at the N-terminal and the length of peptides significantly affect the position of the cleavage site on the oligopeptides, which provides a useful insight for the design of small peptide derivatives as the substrates of MMP-9.

SUBMITTER: Huang Y

PROVIDER: S-EPMC3920740 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Length-dependent proteolytic cleavage of short oligopeptides catalyzed by matrix metalloprotease-9.

Huang Yibing Y Shi Junfeng J Yuan Dan D Zhou Ning N Xu Bing B

Biopolymers 20131101 6

Matrix metalloproteinases (MMPs), as the enzymes to degrade extracellular matrix proteins, play a major role on cell behaviors. Among them, MMP-9 usually catalyzes the degradation of proteins with the dominant cleavage at G/L site. Recent high-throughput screening suggests that S/L is a new major site for the cleavage when the substrates of MMP-9 are oligopeptides. Here we examine the cleavage sites of the N-terminal substituted short oligopeptides as the substrates of MMP-9. As the first exampl ...[more]

PMID: 23520037

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Project description:Treponema pallidum is a highly invasive pathogen that undergoes rapid dissemination to establish widespread infection. Previous investigations identified the T. pallidum adhesin, pallilysin, as an HEXXH-containing metalloprotease that undergoes autocatalytic cleavage and degrades laminin and fibrinogen. In the current study we characterized pallilysin's active site, activation requirements, cellular location, and fibrin clot degradation capacity through both in vitro assays and heterologous treponemal expression and degradation studies. Site-directed mutagenesis showed the pallilysin HEXXH motif comprises at least part of the active site, as introduction of three independent mutations (AEXXH [H¹??A], HAXXH [E¹??A], and HEXXA [H²?²A]) abolished pallilysin-mediated fibrinogenolysis but did not adversely affect host component binding. Attainment of full pallilysin proteolytic activity was dependent upon autocatalytic cleavage of an N-terminal pro-domain, a process which could not occur in the HEXXH mutants. Pallilysin was shown to possess a thrombin cleavage site within its N-terminal pro-domain, and in vitro studies confirmed cleavage of pallilysin with thrombin generates a truncated pallilysin fragment that has enhanced proteolytic activity, suggesting pallilysin can also exploit the host coagulation process to facilitate protease activation. Opsonophagocytosis assays performed with viable T. pallidum demonstrated pallilysin is a target of opsonic antibodies, consistent with a host component-interacting, surface-exposed cellular location. Wild-type pallilysin, but not the HEXXA mutant, degraded fibrin clots, and similarly heterologous expression of pallilysin in the non-invasive spirochete Treponema phagedenis facilitated fibrin clot degradation. Collectively these results identify pallilysin as a surface-exposed metalloprotease within T. pallidum that possesses an HEXXH active site motif and requires autocatalytic or host-mediated cleavage of a pro-domain to attain full host component-directed proteolytic activity. Furthermore, our finding that expression of pallilysin confers upon T. phagedenis the capacity to degrade fibrin clots suggests this capability may contribute to the dissemination potential of T. pallidum.

Dataset Information

Length-dependent proteolytic cleavage of short oligopeptides catalyzed by matrix metalloprotease-9.

Publications

Length-dependent proteolytic cleavage of short oligopeptides catalyzed by matrix metalloprotease-9.

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