ArticleThe Journal of biological chemistry2011
Insights into the molecular activation mechanism of the RhoA-specific guanine nucleotide exchange factor, PDZRhoGEF.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 24 citations in OpenAlex.
- Characterization and computational simulation of human Syx, a RhoGEF implicated in glioblastoma.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2022Article
- Conformational Insights into the Control of CNF1 Toxin Activity by Peptidyl-Prolyl Isomerization: A Molecular Dynamics Perspective.International journal of molecular sciences · 2021Article
- Structural Design and Analysis of the RHOA-ARHGEF1 Binding Mode: Challenges and Applications for Protein-Protein Interface Prediction.Frontiers in molecular biosciences · 2021Article
- GαThe Journal of biological chemistry · 2020Article
- Involvement of the protein kinase Akt2 in insulin-stimulated Rac1 activation leading to glucose uptake in mouse skeletal muscle.PloS one · 2019Article
- Crystal structures of the PH domains from Lbc family of RhoGEFs bound to activated RhoA GTPase.Data in brief · 2018Article
- Phosphoproteomics of cAMP signaling of Bordetella adenylate cyclase toxin in mouse dendritic cells.Scientific reports · 2017Article
- Article
- The crystal structure of the RhoA-AKAP-Lbc DH-PH domain complex.The Biochemical journal · 2014Article
- The emerging role of guanine nucleotide exchange factors in ALS and other neurodegenerative diseases.Frontiers in cellular neuroscience · 2014Review
- Structural basis for autoinhibition of the guanine nucleotide exchange factor FARP2.Structure (London, England : 1993) · 2013Article
- Migration of turkey muscle satellite cells is enhanced by the syndecan-4 cytoplasmic domain through the activation of RhoA.Molecular and cellular biochemistry · 2013Article
- Structural determinants of RGS-RhoGEF signaling critical to Entamoeba histolytica pathogenesis.Structure (London, England : 1993) · 2013Article
- Structure of the Rho-specific guanine nucleotide-exchange factor Xpln.Acta crystallographica. Section F, Structural biology and crystallization communications · 2012Article
- Activation of p115-RhoGEF requires direct association of Gα13 and the Dbl homology domain.The Journal of biological chemistry · 2012Article
- A flexible brace maintains the assembly of a hexameric replicative helicase during DNA unwinding.Nucleic acids research · 2012Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
PDZRhoGEF (PRG) belongs to a small family of RhoA-specific nucleotide exchange factors that mediates signaling through select G-protein-coupled receptors via Gα(12/13) and activates RhoA by catalyzing the exchange of GDP to GTP. PRG is a multidomain protein composed of PDZ, regulators of G-protein signaling-like (RGSL), Dbl-homology (DH), and pleckstrin-homology (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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.