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Protein Science (2007), 16:2570-2577. Published by Cold Spring Harbor Laboratory Press. Copyright © 2007 The Protein Society
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FOR THE RECORD

G{alpha}–Gbeta{gamma} dissociation may be due to retraction of a buried lysine and disruption of an aromatic cluster by a GTP-sensing Arg–Trp pair

Andrew F. Neuwald

J. Craig Venter Institute, Rockville, Maryland 20850, USA

(RECEIVED July 2, 2007; FINAL REVISION August 3, 2007; ACCEPTED August 10, 2007)

The heterotrimeric G protein {alpha} subunit (G{alpha}) functions as a molecular switch by cycling between inactive GDP-bound and active GTP-bound states. When bound to GDP, G{alpha} interacts with high affinity to a complex of the beta and {gamma} subunits (Gbeta{gamma}), but when bound to GTP, G{alpha} dissociates from this complex to activate downstream signaling pathways. G{alpha}'s state is communicated to other cellular components via conformational changes within its switch I and II regions. To identify key determinants of G{alpha}'s function as a signaling pathway molecular switch, a Bayesian approach was used to infer the selective constraints that most distinguish G{alpha} and closely related Arf family GTPases from distantly related translational and metabolic GTPases. The strongest of these constraints are imposed on seven residues within or near the switch II region. Likewise, constraints imposed on G{alpha} but not on other, closely related molecular switches correspond to four nearby residues. These constraints are explained by a proposed mechanism for GTP-induced dissociation of G{alpha} from Gbeta{gamma} where an Arg–Trp pair senses the presence of bound GTP leading to conformational retraction of a nearby lysine and to disruption of an aromatic cluster. Within a complex of Gi{alpha}, Gibeta{gamma}, and GDP, this lysine establishes greater surface contact with Gibeta than does any other residue in Gi{alpha}, whereas the aromatic cluster packs against a highly conserved tryptophan in Gibeta that establishes greater surface contact with Gi{alpha} than does any other residue in Gibeta. Other structural features associated with G{alpha} functional divergence further support the proposed mechanism.

Keywords: structure/function studies; G-proteins (as signal transducers); Arf; Arl; CHAIN analysis


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