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J. Biol. Chem., Vol. 279, Issue 45, 46772-46778, November 5, 2004

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The RGS14 GoLoco Domain Discriminates among G_i Isoforms^*

Vivek Mittal and Maurine E. Linder

From the Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110

Regulators of G protein signaling (RGS) modulate G protein activity by functioning as GTPase-activating proteins (GAPs) for -subunits of heterotrimeric G proteins. RGS14 regulates G protein nucleotide exchange and hydrolysis by acting as a GAP through its RGS domain and as a guanine nucleotide dissociation inhibitor (GDI) through its GoLoco motif. RGS14 exerts GDI activity on G_i1, but not G_o. Selective interactions are mediated by contacts between the A and B helices of the G_i1 helical domain and the GoLoco C terminus (Kimple, R. J., Kimple, M. E., Betts, L., Sondek, J., and Siderovski, D. P. (2002) Nature 416, 878–881). Three isoforms of G_i exist in mammalian cells. In this study, we tested whether all three isoforms were subject to RGS14 GDI activity. We found that RGS14 inhibits guanine nucleotide exchange on G_i1 and G_i3 could, but not G_i2. G_i2 be rendered sensitive to RGS14 GDI activity by replacement of residues within the -helical domain. In addition to the contact residues in the A and B helices previously identified, we found that the A/B and B/C loops are important determinants of G_i selectivity. The striking selectivity observed for RGS14 GDI activity in vitro points to G_i1 and G_i3 as the likely targets of RGS14-GoLoco regulation in vivo.

Received for publication, July 2, 2004 , and in revised form, August 23, 2004.

^* This work was supported by an Established Investigator Award of the American Heart Association (to M. E. L.) and a predoctoral fellowship from the Heartland Affiliate of the American Heart Association (to V. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Cell Biology and Physiology, Washington University School of Medicine, 660 S. Euclid Ave. Campus Box 8228, St. Louis, MO 63110.

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