Glutathionylation Primes Soluble Glyceraldehyde-3-phosphate Dehydrogenase for Late Collapse into Insoluble Aggregates

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2019 Nov 28

PMID 31772010

Citations 20

Authors

Mirko Zaffagnini

Christophe H Marchand

Marco Malferrari

Samuel Murail

Sara Bonacchi

Damiano Genovese

Marco Montalti

Giovanni Venturoli

Giuseppe Falini

Marc Baaden

Stephane D Lemaire

Simona Fermani

Paolo Trost

Affiliations

Soon will be listed here.

Abstract

Protein aggregation is a complex physiological process, primarily determined by stress-related factors revealing the hidden aggregation propensity of proteins that otherwise are fully soluble. Here we report a mechanism by which glycolytic glyceraldehyde-3-phosphate dehydrogenase of (AtGAPC1) is primed to form insoluble aggregates by the glutathionylation of its catalytic cysteine (Cys149). Following a lag phase, glutathionylated AtGAPC1 initiates a self-aggregation process resulting in the formation of branched chains of globular particles made of partially misfolded and totally inactive proteins. GSH molecules within AtGAPC1 active sites are suggested to provide the initial destabilizing signal. The following removal of glutathione by the formation of an intramolecular disulfide bond between Cys149 and Cys153 reinforces the aggregation process. Physiological reductases, thioredoxins and glutaredoxins, could not dissolve AtGAPC1 aggregates but could efficiently contrast their growth. Besides acting as a protective mechanism against overoxidation, S-glutathionylation of AtGAPC1 triggers an unexpected aggregation pathway with completely different and still unexplored physiological implications.

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