title: Structure of protease-cleaved Escherichia coli α-2-macroglobulin reveals a putative mechanism of conformational activation for protease entrapment.
abstract: Bacterial α-2-macroglobulins have been suggested to function in defence as broad-spectrum inhibitors of host proteases that breach the outer membrane. Here, the X-ray structure of protease-cleaved Escherichia coli α-2-macroglobulin is described, which reveals a putative mechanism of activation and conformational change essential for protease inhibition. In this competitive mechanism, protease cleavage of the bait-region domain results in the untethering of an intrinsically disordered region of this domain which disrupts native interdomain interactions that maintain E. coli α-2-macroglobulin in the inactivated form. The resulting global conformational change results in entrapment of the protease and activation of the thioester bond that covalently links to the attacking protease. Owing to the similarity in structure and domain architecture of Escherichia coli α-2-macroglobulin and human α-2-macroglobulin, this protease-activation mechanism is likely to operate across the diverse members of this group.
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland.
authors.forename: Cameron D
authors.initials: CD
authors.lastname: Fyfe
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland.
authors.forename: Rhys
authors.initials: R
authors.lastname: Grinter
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland.
authors.forename: Inokentijs
authors.initials: I
authors.lastname: Josts
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland.
authors.forename: Khedidja
authors.initials: K
authors.lastname: Mosbahi
authors.affiliation: WestCHEM, School of Chemistry, College of Science and Engineering, University of Glasgow, Glasgow G12 8QQ, Scotland.
authors.forename: Aleksander W
authors.initials: AW
authors.lastname: Roszak
authors.affiliation: Institute of Molecular Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Cogdell
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Wall
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland.
authors.forename: Richard J S
authors.initials: RJ
authors.lastname: Burchmore
authors.affiliation: School of Life Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland.
authors.forename: Olwyn
authors.initials: O
authors.lastname: Byron
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Walker
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010196:Pancreatic Elastase / Q000378:metabolism*; D011487:Protein Conformation; D016415:Sequence Alignment; D013552:Swine; D000511:alpha-Macroglobulins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000511:alpha-Macroglobulins; D010196:Pancreatic Elastase
keywords: conformational change; intrinsic disorder; protease inhibitor; α-2-macroglobulin