RRC ID 53690
Author Garcia-Ferrer I, Arêde P, Gómez-Blanco J, Luque D, Duquerroy S, Castón JR, Goulas T, Gomis-Rüth FX.
Title Structural and functional insights into Escherichia coli α2-macroglobulin endopeptidase snap-trap inhibition.
Journal Proc. Natl. Acad. Sci. U.S.A.
Abstract The survival of commensal bacteria requires them to evade host peptidases. Gram-negative bacteria from the human gut microbiome encode a relative of the human endopeptidase inhibitor, α2-macroglobulin (α2M). Escherichia coli α2M (ECAM) is a ∼ 180-kDa multidomain membrane-anchored pan-peptidase inhibitor, which is cleaved by host endopeptidases in an accessible bait region. Structural studies by electron microscopy and crystallography reveal that this cleavage causes major structural rearrangement of more than half the 13-domain structure from a native to a compact induced form. It also exposes a reactive thioester bond, which covalently traps the peptidase. Subsequently, peptidase-laden ECAM is shed from the membrane and may dimerize. Trapped peptidases are still active except against very large substrates, so inhibition potentially prevents damage of large cell envelope components, but not host digestion. Mechanistically, these results document a novel monomeric "snap trap."
Volume 112(27)
Pages 8290-5
Published 2015-7-7
DOI 10.1073/pnas.1506538112
PII 1506538112
PMID 26100869
PMC PMC4500212
MeSH Amino Acid Sequence Binding Sites Crystallography, X-Ray Endopeptidases / metabolism* Escherichia coli / genetics Escherichia coli / metabolism Escherichia coli Proteins / chemistry Escherichia coli Proteins / genetics Escherichia coli Proteins / metabolism* Gastrointestinal Tract / metabolism Gastrointestinal Tract / microbiology Humans Membrane Proteins / chemistry Membrane Proteins / genetics Membrane Proteins / metabolism Microbiota / genetics Microscopy, Electron Models, Molecular Molecular Sequence Data Molecular Weight Peptide Hydrolases / chemistry Peptide Hydrolases / metabolism Protease Inhibitors / chemistry Protease Inhibitors / metabolism* Protein Multimerization Protein Structure, Secondary Protein Structure, Tertiary alpha-Macroglobulins / chemistry alpha-Macroglobulins / genetics alpha-Macroglobulins / metabolism*
IF 9.504
Resource
Prokaryotes E. coli