Modulation of a GEF switch: Autoinhibition of the intrinsic guanine nucleotide exchange activity of p115-RhoGEF

Zhe Chen, Liang Guo, Stephen R. Sprang, Paul C. Sternweis

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


p115-RhoGEF (p115) belongs to the family of RGS-containing guanine nucleotide exchange factors for Rho GTPases (RGS-RhoGEFs) that are activated by G12 class heterotrimeric G protein α subunits. All RGS-RhoGEFs possess tandemly linked Dbl-homology (DH) and plekstrinhomology (PH) domains, which bind and catalyze the exchange of GDP for GTP on RhoA. We have identified that the linker region connecting the N-terminal RGS-homology (RH) domain and the DH domain inhibits the intrinsic guanine nucleotide exchange (GEF) activity of p115, and determined the crystal structures of the DH/PH domains in the presence or absence of the inhibitory linker region. An N-terminal extension of the canonical DH domain (the GEF switch), which is critical to GEF activity, is well folded in the crystal structure of DH/PH alone, but becomes disordered in the presence of the linker region. The linker region is completely disordered in the crystal structure and partially disordered in the molecular envelope calculated from measurements of small angle x-ray scattering (SAXS). It is possible that Gα subunits activate p115 in part by relieving autoinhibition imposed by the linker region.

Original languageEnglish
Pages (from-to)107-117
Number of pages11
JournalProtein Science
Issue number1
StatePublished - Jan 2011


  • DH
  • G12
  • G13
  • GTP-binding protein alpha subunits
  • Guanine nucleotide exchange factors
  • PH
  • RGS proteins
  • Rho GTPase


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