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Title

Structural and functional insights into Escherichia coli α<inf>2</inf> -macroglobulin endopeptidase snap-trap inhibition

AuthorsGarcia-Ferrer, Irene; Arede, Pedro; Gómez-Blanco, Josué; Luque, Daniel; Duquerroy, Stéphane; Castón, José R.; Goulas, Theodoros CSIC ORCID; Gomis-Rüth, F. Xavier CSIC ORCID
Keywordsprotein inhibitor
gut microbiome
conformational rearrangement
X-ray crystal structure
cryo-electron microscopy
Issue Date5-Jul-2015
PublisherNational Academy of Sciences (U.S.)
CitationProceedings of the National Academy of Sciences of the United States of America 112(27): 8290-8295 (2015)
AbstractThe 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, α<inf>2</inf> -macroglobulin (α<inf>2</inf> M). Escherichia coli α<inf>2</inf> M (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.>.
DescriptionThis article contains supporting information online (a detailed description of the experimental procedures is provided in the SI Appendix. The latter also includes four supplementary tables, 10 supplementary figures, the Acknowledgments, and SI Appendix, SRD.) at http://www.pnas.org/content/suppl/2015/06/19/1506538112.DCSupplemental/pnas.1506538112.sapp.pdf
Publisher version (URL)http://dx.doi.org/10.1073/pnas.1506538112
http://www.pnas.org/content/suppl/2015/06/19/1506538112.DCSupplemental/pnas.1506538112.sapp.pdf
URIhttp://hdl.handle.net/10261/124091
DOIhttp://dx.doi.org/10.1073/pnas.1506538112
Identifiersissn: 1091-6490
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