Structural diversity in the RGS domain and its interaction with heterotrimeric G protein alpha-subunits.
Regulator of G protein signaling (RGS) proteins accelerate GTP hydrolysis by Galpha subunits and thus facilitate termination of signaling initiated by G protein-coupled receptors (GPCRs). RGS proteins hold great promise as disease intervention points, given their signature role as negative regulators of GPCRs-receptors to which the largest fraction of approved medications are currently directed. RGS proteins share a hallmark RGS domain that interacts most avidly with Galpha when in its transition state for GTP hydrolysis; by binding and stabilizing switch regions I and II of Galpha, RGS domain binding consequently accelerates Galpha-mediated GTP hydrolysis. The human genome encodes more than three dozen RGS domain-containing proteins with varied Galpha substrate specificities. To facilitate their exploitation as drug-discovery targets, we have taken a systematic structural biology approach toward cataloging the structural diversity present among RGS domains and identifying molecular determinants of their differential Galpha selectivities. Here, we determined 14 structures derived from NMR and x-ray crystallography of members of the R4, R7, R12, and RZ subfamilies of RGS proteins, including 10 uncomplexed RGS domains and 4 RGS domain/Galpha complexes. Heterogeneity observed in the structural architecture of the RGS domain, as well as in engagement of switch III and the all-helical domain of the Galpha substrate, suggests that unique structural determinants specific to particular RGS protein/Galpha pairings exist and could be used to achieve selective inhibition by small molecules.
Soundararajan
Meera
M
Structural Genomics Consortium, Oxford University, Oxford OX3 7DQ, United Kingdom.
Willard
Francis S
FS
Kimple
Adam J
AJ
Turnbull
Andrew P
AP
Ball
Linda J
LJ
Schoch
Guillaume A
GA
Gileadi
Carina
C
Fedorov
Oleg Y
OY
Dowler
Elizabeth F
EF
Higman
Victoria A
VA
Hutsell
Stephanie Q
SQ
Sundström
Michael
M
Doyle
Declan A
DA
Siderovski
David P
DP
D001059:Apoproteins / Q000378:metabolism; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D020710:RGS Proteins / Q000737:chemistry* / Q000378:metabolism*
D001059:Apoproteins; D044385:GTP-Binding Protein alpha Subunits; D021122:Protein Subunits; D020710:RGS Proteins; D043802:GTP-Binding Protein alpha Subunits, Gq-G11