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First published on September 13, 2005; DOI: 10.1124/mol.105.015073

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Received for publication May 24, 2005.
Revised August 24, 2005.
Accepted for publication September 13, 2005.

A key serine for the GTPase-activating protein function of Regulators of G protein Signalling proteins is not a general target for 14-3-3 interactions

Richard J Ward 1 Graeme Milligan 1*

1 University of Glasgow

* Address correspondence to: E-mail: g.milligan{at}bio.gla.ac.uk

Abstract

Mammalian Regulator of G protein Signalling (RGS) proteins are highly conserved within the RGS domain. Of amino acids that are universal, a serine residue at the C-terminus of this domain has been described as the binding site in RGS7 for 14-3-3 proteins. However, studies with the related RGS3 indicate that the site of interaction is not within the RGS domain. We confirm that the interaction of RGS3 with 14-3-3{tau} and 14-3-3{zeta} requires Ser264 and not the RGS domain and show both that mutation of the conserved RGS domain serine, Ser496 in RGS3, to either alanine or aspartate does not prevent binding of 14-3-3 proteins and that 14-3-3 proteins do not inhibit GTPase-activating protein (GAP) activity against receptor-activated G{alpha}o1. However, mutation of Ser496 does directly impair the action of RGS3 as a GAP against receptor-activated G{alpha}o1. We mutated the equivalent serine residue in the family B/R4 RGS proteins RGS1 and RGS16. Using two distinct assay formats conversion to aspartate virtually abolished GAP activity while conversion to alanine decreased potency 20 fold. Neither alteration modulated interactions with 14-3-3{tau} or 14-3-3{zeta} but the 14-3-3 proteins did not modulate the GAP activity of the wild type or mutant RGS proteins. Although interactions between 14-3-3 proteins and many RGS proteins can be observed this does not involve this conserved serine and does not inherently modify GAP function.


Key words: Adrenergic, Gi family, RGS proteins


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