Activated RhoA binds to the Pleckstrin Homology (PH) domain of PDZ-RhoGEF, a potential site for autoregulation

Zhe Chen, Frank Medina, Mu Ya Liu, Celestine Thomas, Stephen R. Sprang, Paul C. Sternweis

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


Guanine nucleotide exchange factors (GEFs) catalyze exchange of GDP for GTP by stabilizing the nucleotide-free state of the small GTPases through their Dbl homology/pleckstrin homology (DH·PH) domains. Unconventionally, PDZ-RhoGEF (PRG), a member of the RGS-RhoGEFs, binds tightly to both nucleotide-free and activated RhoA (RhoA·GTP). We have characterized the interaction between PRG and activated RhoA and determined the structure of the PRG-DH·PH-RhoA·GTPγS (guanosine 5′-O-[γ-thio] triphosphate) complex. The interface bears striking similarity to a GTPase-effector interface and involves the switch regions in RhoA and a hydrophobic patch in PRG-PH that is conserved among all Lbc RhoGEFs. The two surfaces that bind activated and nucleotide-free RhoA on PRGD-H ·PH do not overlap, and a ternary complex of PRG-DH·PH bound to both forms of RhoA can be isolated by size-exclusion chromatography. This novel interaction between activated RhoA and PH could play a key role in regulation of RhoGEF activity in vivo.

Original languageEnglish
Pages (from-to)21070-21081
Number of pages12
JournalJournal of Biological Chemistry
Issue number27
StatePublished - Jul 2 2010


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