Molecular and Structural Basis for Redox Regulation of β-Actin

Abstract

0022-2836/$ see front matter © 2007 E Anessential consequence of growth factor-mediated signal transduction is the generation of intracellular H2O2. It operates as a second messenger in the control of actin microfilament dynamics, causing rapid and dramatic changes in the morphology andmotile activity of stimulated cells. Little is understood about the molecular mechanisms causing these changes in the actin system. Here, it is shown thatH2O2 acts directly upon several levels of this system, and some of the mechanistic effects are detailed. We describe the impact of oxidation on the polymerizability of non-muscleβ/γ-actin and compare with that of muscle α-actin. Oxidation of β/γ-actin can cause a complete loss of polymerizability, crucially, reversible by the thioredoxin system. Further, oxidation of the actin impedes its interaction with profilin and causes depolymerization of filamentous actin. The effects of oxidation are critically dependent on the nucleotide state and the concentration of Ca. We have determined the crystal structure of oxidized β-actin to a resolution of 2.6 Å. The arrangement in the crystal implies an antiparallel homodimer connected by an intermolecular disulfide bond involving cysteine 374. Our data indicate that this dimer forms under non-polymerizing and oxidizing conditions. We identify oxidation of cysteine 272 in the crystallized actin dimer, likely to a cysteine sulfinic acid. In β/γ-actin, this is the cysteine residue most reactive towards H2O2 in solution, and we suggest plausible structural determinants for its reactivity.Noother oxidativemodificationwas obvious in the structure, highlighting the specificity of the oxidation byH2O2. Possible consequences of the observed effects in a cellular context and their potential relevance are discussed. © 2007 Elsevier Ltd. All rights reserved.

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@inproceedings{Lassing2007MolecularAS, title={Molecular and Structural Basis for Redox Regulation of β-Actin}, author={Ingrid Lassing and Florian Schmitzberger and Mikael Bj{\"{o}rnstedt and Arne Holmgren and Paer Nordlund and Clarence Schutt}, year={2007} }