Thiol-based switching mechanisms of stress-sensing chaperones.

Kathrin Ulrich,Ursula Jakob,Blanche Schwappach

doi:10.1515/hsz-2020-0262

Abstract

Thiol-based redox switches evolved as efficient post-translational regulatory mechanisms that enable individual proteins to rapidly respond to sudden environmental changes. While some protein functions need to be switched off to save resources and avoid potentially error-prone processes, protective functions become essential and need to be switched on. In this review, we focus on thiol-based activation mechanisms of stress-sensing chaperones. Upon stress exposure, these chaperones convert into high affinity binding platforms for unfolding proteins and protect cells against the accumulation of potentially toxic protein aggregates. Their chaperone activity is independent of ATP, a feature that becomes especially important under oxidative stress conditions, where cellular ATP levels drop and canonical ATP-dependent chaperones no longer operate. Vice versa, reductive inactivation and substrate release require the restoration of ATP levels, which ensures refolding of client proteins by ATP-dependent foldases. We will give an overview over the different strategies that cells evolved to rapidly increase the pool of ATP-independent chaperones upon oxidative stress and provide mechanistic insights into how stress conditions are used to convert abundant cellular proteins into ATP-independent holding chaperones.

Highlights

Reactive oxygen species, including superoxide anion and hydrogen peroxide are constantly generated in cells living under aerobic conditions
Their chaperone activity is independent of ATP, a feature that becomes especially important under oxidative stress conditions, where cellular ATP levels drop and canonical ATP-dependent chaperones no longer operate
The stress-specific activation of ATP-independent chaperones serves as first line of defense to protect cells from the formation and accumulation of potentially toxic protein aggregates under severe stress conditions

Summary

Introduction

Reactive oxygen species, including superoxide anion and hydrogen peroxide are constantly generated in cells living under aerobic conditions. We will focus on thiol-based switches of redoxregulated chaperones, explore the mechanisms by which these proteins sense oxidative stress, and discuss how redox-dependent conformational changes contribute to their function as molecular chaperones. Fast oxidants, like hypochlorous acid which cause widespread protein unfolding, induce the formation of both disulfide bonds and activate Hsp33’s chaperone function within seconds at any temperature (Winter et al 2008).

Results

Conclusion