title: Structural Basis for Latency and Function of Immune Inhibitor A Metallopeptidase, a Modulator of the Bacillus anthracis Secretome.
abstract: Immune inhibitor A(InhA)-type metallopeptidases are potential virulence factors secreted by members of the Bacillus cereus group. Two paralogs from anthrax-causing Bacillus anthracis (BaInhA1 and BaInhA2) were shown to degrade host tissue proteins with broad substrate specificity. Analysis of their activation mechanism and the crystal structure of a zymogenic BaInhA2 variant revealed a ∼750-residue four-domain structure featuring a pro-peptide, a catalytic domain, a domain reminiscent of viral envelope glycoproteins, and a MAM domain grafted into the latter. This domain, previously found only in eukaryotes, is required for proper protein expression in B. anthracis and evinces certain flexibility. Latency is uniquely modulated by the N-terminal segment of the pro-peptide, which binds the catalytic zinc through its α-amino group and occupies the primed side of the active-site cleft. The present results further our understanding of the modus operandi of an anthrax secretome regulator.
authors.affiliation: Proteolysis Lab, Department of Structural Biology ("María de Maeztu" Unit of Excellence), Molecular Biology Institute of Barcelona, Spanish Research Council (CSIC), Barcelona Science Park, Helix Building, Baldiri Reixac, 15-21, 08028 Barcelona, Spain.
authors.forename: Joan L
authors.initials: JL
authors.lastname: Arolas
authors.affiliation: Proteolysis Lab, Department of Structural Biology ("María de Maeztu" Unit of Excellence), Molecular Biology Institute of Barcelona, Spanish Research Council (CSIC), Barcelona Science Park, Helix Building, Baldiri Reixac, 15-21, 08028 Barcelona, Spain.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Goulas
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Andrei P
authors.initials: AP
authors.lastname: Pomerantsev
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Leppla
authors.affiliation: Proteolysis Lab, Department of Structural Biology ("María de Maeztu" Unit of Excellence), Molecular Biology Institute of Barcelona, Spanish Research Council (CSIC), Barcelona Science Park, Helix Building, Baldiri Reixac, 15-21, 08028 Barcelona, Spain. Electronic address: xgrcri@ibmb.csic.es.
authors.forename: F Xavier
authors.initials: FX
authors.lastname: Gomis-Rüth
mesh_terms: D000595:Amino Acid Sequence; D001408:Bacillus anthracis / Q000201:enzymology*; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020134:Catalytic Domain; D008666:Metalloendopeptidases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D010802:Phylogeny; D011485:Protein Binding; D015032:Zinc / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D008666:Metalloendopeptidases; D015032:Zinc
keywords: anthrax; bacterial infection; crystal structure; metallopeptidase; proteolytic mechanism; regulation