5fr1
Double acetylated RhoGDI-alpha in complex with RhoA-GDPDouble acetylated RhoGDI-alpha in complex with RhoA-GDP
Structural highlights
FunctionRHOA_HUMAN Regulates a signal transduction pathway linking plasma membrane receptors to the assembly of focal adhesions and actin stress fibers. Involved in a microtubule-dependent signal that is required for the myosin contractile ring formation during cell cycle cytokinesis. Plays an essential role in cleavage furrow formation. Required for the apical junction formation of keratinocyte cell-cell adhesion. Serves as a target for the yopT cysteine peptidase from Yersinia pestis, vector of the plague, and Yersinia pseudotuberculosis, which causes gastrointestinal disorders. Stimulates PKN2 kinase activity. May be an activator of PLCE1. Activated by ARHGEF2, which promotes the exchange of GDP for GTP. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. The MEMO1-RHOA-DIAPH1 signaling pathway plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. It controls the localization of APC and CLASP2 to the cell membrane, via the regulation of GSK3B activity. In turn, membrane-bound APC allows the localization of the MACF1 to the cell membrane, which is required for microtubule capture and stabilization.[1] [2] [3] [4] [5] [6] [7] [8] Publication Abstract from PubMedRho 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. 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[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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