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Structure of protease-cleaved Escherichia coli alpha-2-macroglobulin reveals a putative mechanism of conformational activation for protease entrapment

DOI: 10.1107/S1399004715008548 DOI Help
PMID: 26143919 PMID Help

Authors: Cameron Fyfe (University of Glasgow) , Rhys Grinter (University of Glasgow) , Inokentijs Josts (University of Glasgow) , Khedidja Mosbahi (University of Glasgow) , Aleksander Roszak (University of Glasgow) , Richard J. Cogdell (University of Glasgow) , Daniel M. Wall (University of Glasgow) , Richard J. S. Burchmore (University of Glasgow) , Olwyn Byron (University of Glasgow) , Daniel Walker (University of Glasgow)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acta Crystallographica Section D Biological Crystallography , VOL 71 (7) , PAGES 1478 - 1486

State: Published (Approved)
Published: July 2015
Diamond Proposal Number(s): 8659

Open Access Open Access

Abstract: Bacterial alpha-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 alpha-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 alpha-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 alpha-2-macroglobulin and human alpha-2-macroglobulin, this protease-activation mechanism is likely to operate across the diverse members of this group.

Journal Keywords: Alpha-2-Macroglobulin; Protease Inhibitor; Conformational Change; Intrinsic Disorder

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography