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J. Biol. Chem., Vol. 282, Issue 33, 24231-24238, August 17, 2007

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Kelch Repeat Protein Interacts with the Yeast G Subunit Gpa2p at a Site That Couples Receptor Binding to Guanine Nucleotide Exchange^*

From the Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York 10029

The kelch repeat-containing proteins Krh1p and Krh2p are negative regulators of the Gpa2p signaling pathway that directly interact with the G protein -subunit Gpa2p in the yeast Saccharomyces cerevisiae. A screen was carried out to identify Gpa2p variants that are defective in their ability to bind Krh1p but retain the ability to bind another Gpa2p-interacting protein, Ime2p. This screen identified amino acids Gln-419 and Asn-425 as being important for the interaction between Gpa2p and Krh1p. Gpa2p variants with changes at these positions are defective for Krh1p binding in vivo. Cells containing these forms of Gpa2p display decreased heat shock resistance and increased expression of a gene required for pseudohyphal growth. These findings indicate that the substitutions at positions 419 and 425 confer a degree of constitutive activity to the Gpa2p -subunit. Residues Gln-419 and Asn-425 are located in the 6-5 loop and 5 helix of Gpa2p, which is the region that couples receptor binding to guanine nucleotide exchange. The results suggest that binding of Gpa2p to Krh1p does not resemble the binding of G subunits to either G subunits or effectors, but it instead represents a novel type of functional interaction.

Received for publication, March 26, 2007 , and in revised form, June 11, 2007.

^* This work was supported by Grant-in-aid 9951029T from the American Heart Association, Heritage Affiliate, and by Grant GM074242 from the National Institutes of Health. 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.

¹ Present address: Dept. of Medicine, Nephrology Division, Albert Einstein College of Medicine, Bronx, NY 10461.

² Present address: Dept. of Pharmacology, Weill Medical College of Cornell University, New York, NY 10021.

³ To whom correspondence should be addressed: Dept. of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, Box 1603, 1 Gustave L. Levy Place, New York, NY 10029. Tel.: 212-241-0224; Fax: 212-996-7214; E-mail: jeanne.hirsch{at}mssm.edu.

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