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J. Biol. Chem., Vol. 282, Issue 15, 11509-11520, April 13, 2007

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RGK Small GTP-binding Proteins Interact with the Nucleotide Kinase Domain of Ca²⁺-channel -Subunits via an Uncommon Effector Binding Domain^*

From the Epithelial Cell Biology Laboratory, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673, Republic of Singapore

RGK proteins (Kir/Gem, Rad, Rem, and Rem2) form a small subfamily of the Ras superfamily. Despite a conserved GTP binding core domain, several differences suggest that structure, mechanism of action, and functional regulation differ from Ras. RGK proteins down-regulate voltage-gated calcium channel activity by binding in a GTP-dependent fashion to the Ca_v subunits. Mutational analysis combined with homology modeling reveal a novel effector binding mechanism distinct from that of other Ras GTPases. In this model the Switch 1 region acts as an allosteric activator that facilitates electrostatic interactions between Arg-196 in Kir/Gem and Asp-194, -270, and -272 in the nucleotide-kinase (NK) domain of Ca_v3 and wedging Val-223 and His-225 of Kir/Gem into a hydrophobic pocket in the NK domain. Kir/Gem interacts with a surface on the NK domain that is distinct from the groove where the voltage-gated calcium channel Ca_v1 subunit binds. A complex composed of the RGK protein and the Ca_v3 and Ca_v1.2 subunits could be revealed in vivo using coimmunoprecipitation experiments. Intriguingly, docking of the RGK protein to the NK domain of the Ca_v subunit is reminiscent of the binding of GMP to guanylate kinase.

Received for publication, July 6, 2006 , and in revised form, January 9, 2007.

^* This work was supported by the Agency for Science, Technology, and Research, Singapore. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data I-VIII.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 65-6786-9599; Fax: 65-6779-1117; E-mail: Hunziker{at}imcb.a-star.edu.sg.

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