4r3v | pdb_00004r3v
Structure of karilysin propeptide and catalytic MMP domain
Structural highlights
FunctionKLY_TANFA Metalloprotease able to cleave casein, gelatin, elastin, fibrinogen and fibronectin. Shows exclusive preference for hydrophobic residues, especially Leu, Tyr and Met, at the P1' position of substrates, and for Pro or Ala at P3. Can efficiently cleave the antimicrobial peptide LL-37 which is a component of the immune system, leading to a significant reduction of its bactericidal activity. Is also able to inhibit all pathways of the human complement system. The classical and lectin complement pathways are inhibited because of the efficient degradation of mannose-binding lectin, ficolin-2, ficolin-3, and C4 by karilysin, whereas inhibition of the terminal pathway is caused by cleavage of C5. Thus, karilysin appears to be a major virulence factor of T.forsythia that contributes to evasion of the human immune response and periodontal disease. Seems to act synergistically with gingipains from the periodontal pathogen P.gingivalis present at the same sites of infection.[1] [2] [3] [4] Publication Abstract from PubMedThe matrix metalloproteinases (MMPs) are a family of secreted soluble or membrane-anchored multi-modular peptidases regularly found in several paralogous copies in animals and plants, where they have multiple functions. The minimal consensus domain architecture comprises a signal peptide, a 60-to-90-residue globular pro-domain with a conserved sequence motif including a cysteine engaged in cysteine-switch or Velcro mediated latency, and a catalytic domain. Karilysin, from the human periodontopathogen Tannerella forsythia, is the only bacterial MMP to have been characterized biochemically to date. It shares with eukaryotic forms the catalytic domain but none of the flanking domains. Instead of the consensus MMP pro-domain, it features a 14-residue pro-peptide, the shortest reported for a metallopeptidase, which lacks cysteines. Here we determined the structure of a pro-karilysin fragment encompassing the pro-peptide and the catalytic domain, and found that the former runs across the cleft in the opposite direction to a bound substrate and inhibits the latter through an aspartate-switch mechanism. This finding is reminiscent of latency maintenance in the otherwise unrelated astacin and fragilysin metallopeptidase families. In addition, in vivo and biochemical assays showed that the pro-peptide contributes to protein folding and stability. Our analysis of pro-karilysin reveals a novel mechanism of latency and activation in MMPs. Finally, our findings support the view that the karilysin catalytic domain was co-opted by competent bacteria through horizontal gene transfer from a eukaryotic source, and later evolved in a specific bacterial environment. A novel mechanism of latency in matrix metalloproteinases.,L Oacutepez-Pelegrin M, Ksiazek M, Karim AY, Guevara T, Arolas JL, Potempa J, Gomis-R Uumlth FX J Biol Chem. 2015 Jan 2. pii: jbc.M114.605956. PMID:25555916[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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