Folding of a single domain protein entering the endoplasmic reticulum precedes disulfide formation

Robinson, P. J. , Pringle, M. A. , Woolhead, C. A. and Bulleid, N. J. (2017) Folding of a single domain protein entering the endoplasmic reticulum precedes disulfide formation. Journal of Biological Chemistry, 292(17), pp. 6978-6986. (doi: 10.1074/jbc.M117.780742) (PMID:28298446) (PMCID:PMC5409466)

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The relationship between protein synthesis, folding and disulfide formation within the endoplasmic reticulum (ER) is poorly understood. Previous studies have suggested pre-existing disulfide links are absolutely required to allow protein folding and, conversely, that protein folding occurs prior to disulfide formation. To address the question of what happens first within the ER; that is, protein folding or disulfide formation, we studied folding events at the early stages of polypeptide chain translocation into the mammalian ER using stalled translation intermediates. Our results demonstrate that polypeptide folding can occur without complete domain translocation. Protein disulfide isomerase (PDI) interacts with these early intermediates, but disulfide formation does not occur unless the entire sequence of the protein domain is translocated. This is the first evidence that folding of the polypeptide chain precedes disulfide formation within a cellular context and highlights key differences between protein folding in the ER and refolding of purified proteins.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Bulleid, Professor Neil and Pringle, Mrs Marie and Robinson, Dr Philip and Woolhead, Professor Cheryl
Authors: Robinson, P. J., Pringle, M. A., Woolhead, C. A., and Bulleid, N. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Journal of Biological Chemistry
Publisher:American Society for Biochemistry and Molecular Biology, Inc.
ISSN (Online):1083-351X
Published Online:15 March 2017
Copyright Holders:Copyright © 2017 y The American Society for Biochemistry and Molecular Biology, Inc
First Published:First published in Journal of Biological Chemistry 292(17):6978-6986
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
652801Protein Folding and Thiol Modification in the Mammalian Endoplasmic ReticulumNeil BulleidWellcome Trust (WELLCOME)103720/Z/14/ZRI MOLECULAR CELL & SYSTEMS BIOLOGY