Structure of protease-cleaved escherichia coliα-2-macroglobulin reveals a putative mechanism of conformational activation for protease entrapment

Fyfe, C.D., Grinter, R., Josts, I., Mosbahi, K., Roszak, A.W., Cogdell, R.J., Wall, D.M., Burchmore, R.J.S., Byron, O. and Walker, D. (2015) Structure of protease-cleaved escherichia coliα-2-macroglobulin reveals a putative mechanism of conformational activation for protease entrapment. Acta Crystallographica. Section D: Biological Crystallography, 71(7), pp. 1478-1486. (doi:10.1107/s1399004715008548) (PMID:26143919) (PMCID:PMC4498604)

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Abstract

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

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Walker, Professor Daniel and Burchmore, Dr Richard and Cogdell, Professor Richard and Wall, Dr Daniel and Grinter, Mr Rhys and Roszak, Dr Aleksander and Byron, Professor Olwyn and Mosbahi, Dr Khedidja
Authors: Fyfe, C.D., Grinter, R., Josts, I., Mosbahi, K., Roszak, A.W., Cogdell, R.J., Wall, D.M., Burchmore, R.J.S., Byron, O., and Walker, D.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Acta Crystallographica. Section D: Biological Crystallography
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0907-4449
ISSN (Online):1399-0047
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in Acta Crystallographica. Section D: Biological Crystallography 71(7):1478-1486
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
470561DTC in cell and proteomic technologies (continuation)Jonathan CooperEngineering & Physical Sciences Research Council (EPSRC)EP/F500424/1ENG - BIOMEDICAL ENGINEERING
470563DTC in cell and proteomic technologies (continuation)Jonathan CooperEngineering & Physical Sciences Research Council (EPSRC)EP/F500424/1ENG - BIOMEDICAL ENGINEERING
558531Wellcome Trust Studentship 2010-14Daniel WalkerWellcome Trust (WELLCOME)093597/Z/10/ZIII - BACTERIOLOGY
558532Wellcome Trust Studentship 2010-14Daniel WalkerWellcome Trust (WELLCOME)093597/Z/10/ZIII - BACTERIOLOGY