Structural and Mechanistic Insights into the Regulation of the Fundamental Rho Regulator RhoGDI? by Lysine Acetylation.

ABSTRACT: Rho proteins are small GTP/GDP-binding proteins primarily involved in cytoskeleton regulation. Their GTP/GDP cycle is often tightly connected to a membrane/cytosol cycle regulated by the Rho guanine nucleotide dissociation inhibitor ? (RhoGDI?). RhoGDI? has been regarded as a housekeeping regulator essential to control homeostasis of Rho proteins. Recent proteomic screens showed that RhoGDI? is extensively lysine-acetylated. Here, we present the first comprehensive structural and mechanistic study to show how RhoGDI? function is regulated by lysine acetylation. We discover that lysine acetylation impairs Rho protein binding and increases guanine nucleotide exchange factor-catalyzed nucleotide exchange on RhoA, these two functions being prerequisites to constitute a bona fide GDI displacement factor. RhoGDI? acetylation interferes with Rho signaling, resulting in alteration of cellular filamentous actin. Finally, we discover that RhoGDI? is endogenously acetylated in mammalian cells, and we identify CBP, p300, and pCAF as RhoGDI?-acetyltransferases and Sirt2 and HDAC6 as specific deacetylases, showing the biological significance of this post-translational modification.

SUBMITTER: Kuhlmann N 

PROVIDER: S-EPMC4786691 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature