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      Structural and functional insights into Escherichia coli α2-macroglobulin endopeptidase snap-trap inhibition.

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          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."

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          Author and article information

          Journal
          Proc Natl Acad Sci U S A
          Proceedings of the National Academy of Sciences of the United States of America
          Proceedings of the National Academy of Sciences
          1091-6490
          0027-8424
          Jul 07 2015
          : 112
          : 27
          Affiliations
          [1 ] Proteolysis Lab, Department of Structural Biology ("María de Maeztu" Unit of Excellence), Molecular Biology Institute of Barcelona, Spanish Research Council (CSIC), 08028 Barcelona, Spain;
          [2 ] Department of Structure of Macromolecules, Centro Nacional de Biotecnología, CSIC, 28049 Madrid, Spain;
          [3 ] Department of Structure of Macromolecules, Centro Nacional de Biotecnología, CSIC, 28049 Madrid, Spain; Spanish National Microbiology Centre, Institute of Health Carlos III, 28220 Madrid, Spain;
          [4 ] Unité de Virologie Structurale, Département de Virologie and CNRS Unité de Recherche Associée 3015, Institut Pasteur, 75724 Paris Cedex 15, France; Departement de Biologie, Faculté des Sciences d'Orsay, Université Paris-Sud, 91405 Orsay, France.
          [5 ] Proteolysis Lab, Department of Structural Biology ("María de Maeztu" Unit of Excellence), Molecular Biology Institute of Barcelona, Spanish Research Council (CSIC), 08028 Barcelona, Spain; thgcri@ibmb.csic.es xgrcri@ibmb.csic.es.
          Article
          1506538112
          10.1073/pnas.1506538112
          4500212
          26100869
          895c7265-e9f0-4862-9d7c-e8fc2500117b
          History

          X-ray crystal structure,conformational rearrangement,cryo-electron microscopy,gut microbiome,protein inhibitor

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