A Novel Mechanism of Latency in Matrix Metalloproteinases

摘要: The matrix metalloproteinases (MMPs) are a family of secreted soluble or membrane-anchored multimodular peptidases regularly found in several paralogous copies animals and plants, where they have multiple functions. minimal consensus domain architecture comprises signal peptide, 60-90-residue globular prodomain with conserved sequence motif including cysteine engaged "cysteine-switch" "Velcro" mediated latency, catalytic domain. Karilysin, from the human periodontopathogen Tannerella forsythia, is only bacterial MMP to been characterized biochemically date. It shares eukaryotic forms but none flanking domains. Instead prodomain, it features 14-residue propeptide, shortest reported for metallopeptidase, which lacks cysteines. Here we determined structure prokarilysin fragment encompassing propeptide domain, that former runs across cleft opposite direction bound substrate inhibits latter through an "aspartate-switch" mechanism. This finding reminiscent latency maintenance otherwise unrelated astacin fragilysin metallopeptidase families. In addition, vivo biochemical assays showed contributes protein folding stability. Our analysis reveals novel mechanism activation MMPs. Finally, our findings support view karilysin was co-opted by competent bacteria horizontal gene transfer source, later evolved specific environment.