Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1964391 | Cellular Signalling | 2008 | 14 Pages |
Abstract
Regulator of G protein signaling (RGS) proteins play a crucial role in the adaptation of cells to stimulation by G protein-coupled receptors via heterotrimeric G proteins. Alterations in RGS function have been implicated in a wide range of disease states, leading to many researchers focusing on controlling the action of these regulatory proteins. Previous studies have centered on reducing or inhibiting the action of RGS proteins, utilizing inactive mutants or small molecular RGS inhibitors. Here we describe the isolation and characterization of a novel human RGS4 mutant which displays enhanced or gain-of-function (GOF) activity. RGS4S30C demonstrates GOF activity both in an in vivo yeast-based signalling pathway and in vitro against the Gαo1 subunit contained in an α2A-adrenoreceptor-Gαo1C351I fusion protein. Mutational analysis of serine 30 identified a number of alternative substitutions that result in GOF activity. GOF activity was retained upon transposition of the serine 30-cysteine mutation to the equivalent serine residue in human RGS16. As with previously identified GOF mutants, RGS4S30C/S30F/S30K demonstrate increased steady state protein levels, however these mutants also demonstrate enhanced GAP activity through an additional mechanism distinct from the increased protein content. The identification of human RGS mutants with GOF activity may provide novel therapeutic agents for the treatment of signaling-based diseases and the ability to transpose these mutations to other human RGS proteins extends their application to multiple pathways.
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Authors
Claire Hill, Zoe Brownlie, John Davey, Graeme Milligan, Graham Ladds,