4R3V

Structure of karilysin propeptide and catalytic MMP domain

Summary for 4R3V

• Entry DOI: 10.2210/pdb4r3v/pdb
• Related: 2XS3 2XS4 4IN9
• Descriptor: Karilysin, ZINC ION, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: metzincin metallopeptidase, matrix metalloproteinase with unique propeptide, bacterial matrix metalloproteinase-like enzyme, hydrolase
• Biological source: Tannerella forsythia
• Cellular location: Secreted : D0EM77
• Total number of polymer chains: 2
• Total formula weight: 41394.91

Authors

Lopez-Pelegrin, M.,Ksiazek, M.,Karim, A.Y.,Guevara, T.,Arolas, J.L.,Potempa, J.,Gomis-Ruth, F.X. (deposition date: 2014-08-18, release date: 2015-01-07, Last modification date: 2023-09-20)

Primary citation

Lopez-Pelegrin, M.,Ksiazek, M.,Karim, A.Y.,Guevara, T.,Arolas, J.L.,Potempa, J.,Gomis-Ruth, F.X.
A novel mechanism of latency in matrix metalloproteinases.
J.Biol.Chem., 290:4728-4740, 2015

PubMed Abstract: The matrix metalloproteinases (MMPs) are a family of secreted soluble or membrane-anchored multimodular 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 60-90-residue globular prodomain 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 prodomain, it features a 14-residue propeptide, the shortest reported for a metallopeptidase, which lacks cysteines. Here we determined the structure of a prokarilysin fragment encompassing the propeptide 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 propeptide contributes to protein folding and stability. Our analysis of prokarilysin 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.

PubMed: 25555916
DOI: 10.1074/jbc.M114.605956

Experimental method

X-RAY DIFFRACTION (2.01 Å)