期刊
PROTEIN SCIENCE
卷 20, 期 1, 页码 107-117出版社
WILEY
DOI: 10.1002/pro.542
关键词
GTP-binding protein alpha subunits; G12; G13; Rho GTPase; guanine nucleotide exchange factors; RGS proteins; DH; PH
资金
- National Institute of Health [GM31954, DK46371]
- Welch foundation [I-1262]
- Alfred and Mabel Gilman Chair in Molecular Pharmacology
- U.S. Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357]
- U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-ENG-38]
- National Institutes of Health [RR-08630]
- NATIONAL CENTER FOR RESEARCH RESOURCES [P41RR008630] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM031954] Funding Source: NIH RePORTER
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 alpha subunits. All RGS-RhoGEFs possess tandemly linked Dbl-homology (DH) and plekstrin-homology (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 G alpha subunits activate p115 in part by relieving autoinhibition imposed by the linker region.
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