Short talk:
Redox-regulated chaperones in cell stress responses

Kathrin Ulrich1, Ákos Farkas2, Olivia Chan1, Olivia Katamanin1, Blanche Schwappach2, Ursula Jakob1

1Univeristy of Michigan, Department of Molecular, Cellular, and Developmental Biology , Ann Arbor, United States,
2Universitätsmedizin Göttingen, Department of Molecular Biology, Göttingen, Germany

Protein unfolding and aggregation have long been associated with premature aging and disease development. Oxidative stress is a major cause of protein unfolding. Due to the concomitant drop in cellular ATP levels, the function of ATP-dependent chaperones and proteases is impaired. To counteract the severe risk of protein aggregation under these conditions, cells immediately activate a pool of highly abundant proteins as ATP-independent chaperones that bind unfolding protein intermediates and prevent their aggregation. We recently discovered how the highly conserved, eukaryotic protein Get3, which functions as an ATP-dependent targeting factor for tail-anchored membrane proteins under non-stress conditions, becomes activated as a molecular chaperone upon oxidative stress. The chaperone function is tightly regulated by its nucleotide-binding state and the redox status of two conserved cysteines. Nucleotide-binding determines the accessibility and/or reactivity of the redox-sensitive cysteines. Thiol oxidation locks the protein in a nucleotide-free state, causes local unfolding and the formation of chaperone-active oligomers. Accordingly, chaperone inactivation depends on the reduction of Get3’s cysteines followed by ATP-binding, which is essential for the transfer of client proteins to the ATP-dependent Hsp70/Hsp40 system for refolding as soon as non-stress conditions have been restored. Manipulating this highly orchestrated switching mechanism prevents client release and causes a growth defect and increased sensitivity towards oxidative stress in yeast cells. We recently found that the functional switch is conserved in the human homolog Asna1/TRC40, which protects the cells against oxidative stress.

 

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