Robinson, P. J. , Kanemura, S., Cao, X. and Bulleid, N. J. (2020) Protein secondary structure determines the temporal relationship between folding and disulfide formation. Journal of Biological Chemistry, 295(8), pp. 2438-2448. (doi: 10.1074/jbc.RA119.011983) (PMID:31953323) (PMCID:PMC7039548)
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Abstract
How and when disulfides bonds form in proteins relative to the stage of their folding is a fundamental question in cell biology. Two models describe this relationship, the folded precursor model, in which a nascent structure forms before disulfides do and the quasi-stochastic model where disulfides form prior to folding. Here we investigated oxidative folding of three structurally diverse substrates, β2-microglobulin (β2M), prolactin, and the disintegrin domain of ADAM metallopeptidase domain 10 (ADAM10), to understand how these mechanisms apply in a cellular context. We used a eukaryotic cell-free translation system in which we could identify disulfide isomers in stalled translation intermediates to characterize (i) the timing of disulfide formation relative to translocation into the endoplasmic reticulum and (ii) the presence of non-native disulfides. Our results indicate that in a domain lacking secondary structure, disulfides form before conformational folding through a process prone to non-native disulfide formation, whereas in proteins with defined secondary structure, native disulfide formation occurs after partial folding. These findings reveal that the nascent protein structure promotes correct disulfide formation during co-translational folding.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Bulleid, Professor Neil and Cao, Xiaofei and Robinson, Dr Philip |
| Authors: | Robinson, P. J., Kanemura, S., Cao, X., and Bulleid, N. J. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Molecular Biosciences |
| Journal Name: | Journal of Biological Chemistry |
| Publisher: | American Society for Biochemistry and Molecular Biology, Inc. |
| ISSN: | 0021-9258 |
| ISSN (Online): | 1083-351X |
| Published Online: | 17 January 2020 |
| Copyright Holders: | Copyright © 2020 Robinson et al. |
| First Published: | First published in Journal of Biological Chemistry 295(8):2438-2448 |
| Publisher Policy: | Reproduced under a Creative Commons license |
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