title: The structure of the catalytic domain of Tannerella forsythia karilysin reveals it is a bacterial xenologue of animal matrix metalloproteinases.
abstract: Metallopeptidases (MPs) are among virulence factors secreted by pathogenic bacteria at the site of infection. One such pathogen is Tannerella forsythia, a member of the microbial consortium that causes peridontitis, arguably the most prevalent infective chronic inflammatory disease known to mankind. The only reported MP secreted by T. forsythia is karilysin, a 52 kDa multidomain protein comprising a central 18 kDa catalytic domain (CD), termed Kly18, flanked by domains unrelated to any known protein. We analysed the 3D structure of Kly18 in the absence and presence of Mg(2+) or Ca(2+) , which are required for function and stability, and found that it evidences most of the structural features characteristic of the CDs of mammalian matrix metalloproteinases (MMPs). Unexpectedly, a peptide was bound to the active-site cleft of Kly18 mimicking a left-behind cleavage product, which revealed that the specificity pocket accommodates bulky hydrophobic side-chains of substrates as in mammalian MMPs. In addition, Kly18 displayed a unique Mg(2+) or Ca(2+) binding site and two flexible segments that could play a role in substrate binding. Phylogenetic and sequence similarity studies revealed that Kly18 is evolutionarily much closer to winged-insect and mammalian MMPs than to potential bacterial counterparts found by genomic sequencing projects. Therefore, we conclude that this first structurally characterized non-mammalian MMP is a xenologue co-opted through horizontal gene transfer during the intimate coexistence between T. forsythia and humans or other animals, in a very rare case of gene shuffling from eukaryotes to prokaryotes. Subsequently, this protein would have evolved in a bacterial environment to give rise to full-length karilysin that is furnished with unique flanking domains that do not conform to the general multidomain architecture of animal MMPs.
authors.affiliation: Proteolysis Lab, Department of Structural Biology, Molecular Biology Institute of Barcelona, CSIC, Barcelona Science Park, Helix Building, c/ Baldiri Reixac, 15-21, E-08028 Barcelona, Catalunya, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Cerdà-Costa
authors.forename: Tibisay
authors.initials: T
authors.lastname: Guevara
authors.forename: Abdulkarim Y
authors.initials: AY
authors.lastname: Karim
authors.forename: Miroslaw
authors.initials: M
authors.lastname: Ksiazek
authors.forename: Ky-Anh
authors.initials: KA
authors.lastname: Nguyen
authors.forename: Joan L
authors.initials: JL
authors.lastname: Arolas
authors.forename: Jan
authors.initials: J
authors.lastname: Potempa
authors.forename: F Xavier
authors.initials: FX
authors.lastname: Gomis-Rüth
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D041963:Bacteroidetes / Q000201:enzymology*; D002118:Calcium / Q000378:metabolism; D020134:Catalytic Domain; D002413:Cations, Divalent / Q000378:metabolism; D003067:Coenzymes / Q000378:metabolism; D018360:Crystallography, X-Ray; D019143:Evolution, Molecular; D007313:Insecta / Q000201:enzymology; D008274:Magnesium / Q000378:metabolism; D008322:Mammals; D020782:Matrix Metalloproteinases / Q000737:chemistry* / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010802:Phylogeny; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: D002413:Cations, Divalent; D003067:Coenzymes; D020782:Matrix Metalloproteinases; D008274:Magnesium; D002118:Calcium