5fr2 | pdb_00005fr2
Farnesylated RhoA-GDP in complex with RhoGDI-alpha, lysine acetylated at K178
Structural highlights
Function[RHOA_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] [GDIR1_BOVIN] In glioma cells, inhibits cell migration and invasion by mediating the signals of SEMA5A and PLXNB3 that lead to inactivation of RAC1 (By similarity). Regulates the GDP/GTP exchange reaction of the Rho proteins by inhibiting the dissociation of GDP from them, and the subsequent binding of GTP to them.[9] [10] Publication Abstract from PubMedRho-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. 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[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||||
