期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 285, 期 27, 页码 21070-21081出版社
ELSEVIER
DOI: 10.1074/jbc.M110.122549
关键词
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资金
- National Institutes of Health [GM31954, DK46371]
- Robert A. Welch Foundation [I-1262]
- Alfred and Mabel Gilman Chair in Molecular Pharmacology
- United States Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357]
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.GTP gamma S (guanosine 5'-O-[gamma-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 PRG-DH.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.
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