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Molecular and Cellular Biology, June 2003, p. 3847-3858, Vol. 23, No. 11
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.11.3847-3858.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Identification of Tetratricopeptide Repeat 1 as an Adaptor Protein That Interacts with Heterotrimeric G Proteins and the Small GTPase Ras

Caroline Marty, Darren D. Browning,{dagger} and Richard D. Ye*

Department of Pharmacology, College of Medicine, University of Illinois, Chicago, Illinois 60612

Received 14 June 2002/ Returned for modification 2 August 2002/ Accepted 14 March 2003

The biological functions of heterotrimeric G proteins and small GTPases are modulated by both extracellular stimuli and intracellular regulatory proteins. Using Saccharomyces cerevisiae two-hybrid screening, we identified tetratricopeptide repeat 1 (TPR1), a 292-amino-acid protein with three TPR motifs, as a G{alpha}16-binding protein. The interaction was confirmed both in vitro and in transfected mammalian cells, where TPR1 also binds to several other G{alpha} proteins. TPR1 was found to interact with Ha-Ras preferentially in its active form. Overexpression of TPR1 promotes accumulation of active Ras. TPR1 was found to compete with the Ras-binding domain (RBD) of Raf-1 for binding to the active Ras, suggesting that it may also compete with Ras GTPase-activating protein, thus contributing to the accumulation of GTP-bound Ras. Expression of G{alpha}16 strongly enhances the interaction between TPR1 and Ras. Removal of the TPR1 N-terminal 112 residues abolishes potentiation by G{alpha}16 while maintaining the interaction with G{alpha}16 and the ability to discriminate active Ras from wild-type Ras. We have also observed that LGN, a G{alpha}i-interacting protein with seven TPR motifs, binds Ha-Ras. Thus, TPR1 is a novel adaptor protein for Ras and selected G{alpha} proteins that may be involved in protein-protein interaction relating to G-protein signaling.

* Corresponding author. Mailing address: Department of Pharmacology, University of Illinois at Chicago, 835 S. Wolcott Ave., Chicago, IL 60612. Phone: (312) 996-5087. Fax: (312) 996-7857. E-mail: yer{at}uic.edu.

{dagger} Present address: Department of Biochemistry, Medical College of Georgia, Augusta, Ga.

Molecular and Cellular Biology, June 2003, p. 3847-3858, Vol. 23, No. 11
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.11.3847-3858.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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