Oxidative Folding of Proteins: Basic Principles, Cellular Regulation and Engineering
CHAPTER 4.3: Redox Regulation of Hsp70 Chaperone Function in the Endoplasmic Reticulum
Published:27 Jul 2018
Special Collection: 2018 ebook collectionSeries: Chemical Biology
C. S. Sevier, in Oxidative Folding of Proteins: Basic Principles, Cellular Regulation and Engineering, ed. M. J. Feige, The Royal Society of Chemistry, 2018, pp. 334-354.
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Fluctuations in the redox environment of the endoplasmic reticulum (ER) can disrupt the efficiency and fidelity of secretory protein biogenesis. Overly reducing conditions limit protein folding by preventing disulfide bond formation; overly oxidizing conditions can result in the accumulation of potentially toxic misoxidized and misfolded polypeptides. Key to the maintenance of proper folding across a range of environmental and physiological conditions are systems that buffer against ER redox changes. This chapter discusses a newly emerging mechanism used by cells to sense and respond to overly oxidizing ER redox conditions: post-translational oxidation of the ER Hsp70 chaperone BiP. First, the established importance of BiP (immunoglobulin-binding protein) in ER folding homeostasis under non-stress conditions is outlined, followed by a discussion of how the modification (oxidation) of BiP serves to promote cell survival during overly oxidizing ER conditions. The mechanisms for redox adduct formation during oxidative stress are outlined, and also the systems for BiP adduct removal when stress subsides. The chapter ends with a discussion of future research avenues that stem from the current understanding of BiP as a sensor of ER redox changes.