5fr2

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== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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Rho proteins are major regulators of the cytoskeleton. As most Ras-related proteins, they switch between an active, GTP-bound and an inactive, GDP-bound conformation. Rho proteins are targeted to the plasma membrane via a polybasic region and a prenyl group attached to a C-terminal cysteine residue. To distribute Rho proteins in the cell, the molecular chaperone RhoGDIalpha binds to the prenylated Rho proteins forming a cytosolic pool of mainly GDP-loaded Rho. Most studies characterized the interaction of prenylated Rho proteins and RhoGDIalpha. However, RhoGDIalpha was also shown to bind to nonprenylated Rho proteins with physiologically relevant micomolar affinities. Recently, it was discovered that RhoGDIalpha is targeted by post-translational lysine acetylation. For one site, K141, it was hypothesized that acetylation might lead to increased levels of formation of filamentous actin and filopodia in mammalian cells. The functional consequences of lysine acetylation for the interplay with nonprenylated RhoA have not been investigated. Here, we report that lysine acetylation at lysines K127 and K141 in the RhoGDIalpha immunoglobulin domain interferes with the interaction toward nonprenylated RhoA using a combined biochemical and biophysical approach. We determined the first crystal structure of a doubly acetylated protein, RhoGDIalpha, in complex with RhoA.GDP. We discover that the C-terminus of RhoA adopts a different conformation forming an intermolecular beta-sheet with the RhoGDIalpha immunoglobulin domain.
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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 alpha (RhoGDIalpha). RhoGDIalpha has been regarded as a housekeeping regulator essential to control homeostasis of Rho-proteins. Recent proteomic screens showed that RhoGDIalpha is extensively lysine acetylated. Here, we present the first comprehensive structural and mechanistic study to show how RhoGDIalpha function is regulated by lysine acetylation. We discover that lysine acetylation impairs Rho-protein binding and increases GEF-catalysed nucleotide exchange on RhoA, being prerequisites to constitute a bona fide GDI-displacement factor. RhoGDIalpha-acetylation interferes with Rho-signalling resulting in alteration of cellular filamentous actin. Finally, we discover that RhoGDIalpha is endogenously acetylated in mammalian cells, we identify CBP, p300, pCAF as RhoGDIalpha-acetyltransferases and Sirt2, HDAC6 as specific deacetylases, showing the biological significance of this post-translational modification.
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RhoGDIalpha Acetylation at K127 and K141 Affects Binding toward Nonprenylated RhoA.,Kuhlmann N, Wroblowski S, Scislowski L, Lammers M Biochemistry. 2016 Jan 4. PMID:26695096<ref>PMID:26695096</ref>
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Structural and mechanistic insights into the regulation of the fundamental Rho-regulator RhoGDIalpha by lysine acetylation.,Kuhlmann N, Wroblowski S, Knyphausen P, de Boor S, Brenig J, Zienert AY, Meyer-Teschendorf K, Praefcke GJ, Nolte H, Kruger M, Schacherl M, Baumann U, James LC, Chin JW, Lammers M J Biol Chem. 2015 Dec 30. pii: jbc.M115.707091. PMID:26719334<ref>PMID:26719334</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

Revision as of 18:27, 27 January 2016

Farnesylated RhoA-GDP in complex with RhoGDI-alpha, lysine acetylated at K178

5fr2, resolution 3.35Å

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