3P24

Structure of profragilysin-3 from Bacteroides fragilis

Summary for 3P24

• Entry DOI: 10.2210/pdb3p24/pdb
• Descriptor: BFT-3, TETRAETHYLENE GLYCOL, GLYCEROL, ... (6 entities in total)
• Functional Keywords: metzincins, metalloendopeptidase, hydrolase
• Biological source: Bacteroides fragilis
• Total number of polymer chains: 4
• Total formula weight: 179116.57

Authors

Goulas, T.,Arolas, J.L.,Gomis-Ruth, F.X. (deposition date: 2010-10-01, release date: 2010-12-29, Last modification date: 2024-02-21)

Primary citation

Goulas, T.,Arolas, J.L.,Gomis-Ruth, F.X.
Structure, function and latency regulation of a bacterial enterotoxin potentially derived from a mammalian adamalysin/ADAM xenolog.
Proc.Natl.Acad.Sci.USA, 108:1856-1861, 2011

PubMed Abstract: Enterotoxigenic Bacteroides fragilis is the most frequent disease-causing anaerobe in the intestinal tract of humans and livestock and its specific virulence factor is fragilysin, also known as B. fragilis toxin. This is a 21-kDa zinc-dependent metallopeptidase existing in three closely related isoforms that hydrolyze E-cadherin and contribute to secretory diarrhea, and possibly to inflammatory bowel disease and colorectal cancer. Here we studied the function and zymogenic structure of fragilysin-3 and found that its activity is repressed by a ∼170-residue prodomain, which is the largest hitherto structurally characterized for a metallopeptidase. This prodomain plays a role in both the latency and folding stability of the catalytic domain and it has no significant sequence similarity to any known protein. The prodomain adopts a novel fold and inhibits the protease domain via an aspartate-switch mechanism. The catalytic fragilysin-3 moiety is active against several protein substrates and its structure reveals a new family prototype within the metzincin clan of metallopeptidases. It shows high structural similarity despite negligible sequence identity to adamalysins/ADAMs, which have only been described in eukaryotes. Because no similar protein has been found outside enterotoxigenic B. fragilis, our findings support that fragilysins derived from a mammalian adamalysin/ADAM xenolog that was co-opted by B. fragilis through a rare case of horizontal gene transfer from a eukaryotic cell to a bacterial cell. Subsequently, this co-opted peptidase was provided with a unique chaperone and latency maintainer in the time course of evolution to render a robust and dedicated toxin to compromise the intestinal epithelium of mammalian hosts.

PubMed: 21233422
DOI: 10.1073/pnas.1012173108

Experimental method

X-RAY DIFFRACTION (1.8 Å)