3t06
From Proteopedia
Crystal Structure of the DH/PH fragment of PDZRHOGEF with N-terminal regulatory elements in complex with Human RhoA
Structural highlights
Function[ARHGB_HUMAN] May play a role in the regulation of RhoA GTPase by guanine nucleotide-binding alpha-12 (GNA12) and alpha-13 (GNA13). Acts as guanine nucleotide exchange factor (GEF) for RhoA GTPase and may act as GTPase-activating protein (GAP) for GNA12 and GNA13. [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] Publication Abstract from PubMedPDZRhoGEF (PRG) belongs to a small family of RhoA-specific nucleotide exchange factors, which mediate signaling through select G-protein coupled receptors (GPCRs) via Galpha12/13, and activate RhoA by catalyzing the exchange of GDP to GTP. PRG is a multidomain protein composed of PDZ, RGSL, DH and PH domains. It is autoinhibited in cytosol, and is believed to undergo a conformational rearrangement and translocation to the membrane for full activation, although the molecular details of the regulation mechanism are not clear. It has been shown recently, that the main autoregulatory elements of PDZRhoGEF - the autoinhibitory 'activation box' and the 'GEF switch', which is required for full activation, are located directly upstream of the catalytic DH domain and its RhoA-binding surface, emphasizing the functional role of the RGSL-DH linker. Here, using a combination of biophysical and biochemical methods, we show that the mechanism of PRG regulation is yet more complex, and may involve an additional autoinhibitory element in the form of a molten globule region within the linker between RGSL and DH domains. We propose a novel, two-tier model of autoinhibition, where the 'activation box' and the molten globule region act synergistically to impair the ability of RhoA to bind to the catalytic DH-PH tandem. The molten globule region and the 'activation box' become less ordered in the PRG/RhoA complex, and dissociate from the RhoA binding site, which may constitute a critical step leading to PRG activation. Insights into the molecular activation mechanism of the RhoA-specific guanine nucleotide exchange factor, PDZRhoGEF.,Bielnicki JA, Shkumatov A, Derewenda U, Somlyo AV, Svergun DI, Derewenda ZS J Biol Chem. 2011 Aug 4. PMID:21816819[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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