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J. Biol. Chem., Vol. 281, Issue 40, 30234-30241, October 6, 2006

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Signal Transfer from GPCRs to G Proteins

ROLE OF THE G N-TERMINAL REGION IN RHODOPSIN-TRANSDUCIN COUPLING^*

Rolf Herrmann¹², Martin Heck¹, Peter Henklein, Klaus Peter Hofmann^¶, and Oliver P. Ernst³

From the Institut für Medizinische Physik und Biophysik and Institut für Biochemie, Charité-Universitätsmedizin Berlin, Schumannstrasse 20/21, D-10098 Berlin, Germany and ^¶Zentrum für Biophysik und Bioinformatik, Humboldt-Universität zu Berlin, Invalidenstrasse 42, D-10015 Berlin, Germany

Catalysis of nucleotide exchange in heterotrimeric G proteins (G) is a key step in cellular signal transduction mediated by G protein-coupled receptors. The G N terminus with its helical stretch is thought to be crucial for G protein/activated receptor (R^*) interaction. The N-terminal fatty acylation of G is important for membrane targeting of G proteins. By applying biophysical techniques to the rhodopsin/transducin model system, we studied the effect of N-terminal truncations in G. In G, lack of the fatty acid and G truncations up to 33 amino acids had little effect on R^* binding and R^*-catalyzed nucleotide exchange, implying that this region is not mandatory for R^*/G interaction. However, when the other hydrophobic modification of G, the G C-terminal farnesyl moiety, is lacking, R^* interaction requires the fatty acylated G N terminus. This suggests that the two hydrophobic extensions can replace each other in the interaction of G with R^*. We propose that in native G, these two terminal regions are functionally redundant and form a microdomain that serves both to anchor the G protein to the membrane and to establish an initial docking complex with R^*. Accordingly, we find that the native fatty acylated G is competent to interact with R^* even in the absence of G, whereas nonacylated G requires G for interaction. Experiments with N-terminally truncated G subunits suggest that in the second step of the catalytic process, the receptor binds to the N/1-loop region of G to reduce nucleotide affinity and to make the G C terminus available for subsequent interaction with R^*.

Received for publication, January 26, 2006 , and in revised form, July 7, 2006.

^* This research was supported by Deutsche Forschungsgemeinschaft Grant SFB 449. 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 These authors contributed equally to this work.

² Present address: Duke University Eye Center, 5000 AERI, Erwin Rd., Durham NC 27710.

³ To whom correspondence should be addressed: Institut für Medizinische Physik und Biophysik, Charité-Universitätsmedizin Berlin, Schumann Strasse 20/21, D-10098 Berlin, Germany. Tel.: 49-30-450-524-111; Fax: 49-30-450-524-952; E-mail: oliver.ernst{at}charite.de.

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