@article{6aea14dae50d45ca867d064a6b8dfd84,
title = "Structural determinants for GoLoco-induced inhibition of nucleotide release by Gα subunits",
abstract = "Heterotrimeric G-proteins bind to cell-surface receptors and are integral in transmission of signals from outside the cell. Upon activation of the Gα subunit by binding of GTP, the Gα and Gβγ subunits dissociate and interact with effector proteins for signal transduction. Regulatory proteins with the 19-amino-acid GoLoco motif can bind to Gα subunits and maintain G-protein subunit dissociation in the absence of Gα activation. Here we describe the structural determinants of GoLoco activity as revealed by the crystal structure of Gαi1-GDP bound to the GoLoco region of the 'regulator of G-protein signalling' protein RGS14. Key contacts are described between the GoLoco motif and Gα protein, including the extension of GoLoco's highly conserved Asp/Glu-Gln-Arg triad into the nucleotide-binding pocket of Gα to make direct contact with the GDP α- and β-phosphates. The structural organization of the GoLoco-Gαi1 complex, when combined with supporting data from domain-swapping experiments, suggests that the Gα all-helical domain and GoLocoregion carboxy-terminal residues control the specificity of GoLoco-Gα interactions.",
author = "Kimple, {Randall J.} and Kimple, {Michelle E.} and Laurie Betts and John Sondek and Siderovski, {David P.}",
note = "Funding Information: We thank R. Neubig for supplying the Ga chimaeras GoGiGo and GiGoGi, members of the Siderovski and Sondek laboratories for technical assistance and support, and T. K. Harden for comments and enthusiasm. R.J.K. is supported by a predoctoral fellowship from the National Institute of Mental Health. J.S. acknowledges support from the National Institutes of Health (NIH) and the Pew Charitable Trusts. D.P.S. is a Year 2000 Scholar of the EJLB Foundation, recipient of the Burroughs–Wellcome Fund New Investigator Award in the Pharmacological Sciences, and acknowledges additional grant support from the NIH. Funding Information: We thank J. Faulhaber and H. Ehmke for blood gas analysis; M. B{\"o}sl for blastocyst injection and implantation; M. Knipper for the prestin antiserum; M. Knepper for the aquaporin 2 antiserum; S. Gluck for the proton ATPase antiserum; M. Kolster, B. Dierkes and I. {\"O}zt{\"u}rk for technical assistance; H. Voss for taking care of animals; and U. Koch for support. This work was supported by grants from the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen Industrie, and the Prix Louis-Jeantet de M{\'e}decine to T.J.J.",
year = "2002",
month = apr,
day = "25",
doi = "10.1038/416878a",
language = "English",
volume = "416",
pages = "878--881",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "6883",
}