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J. Biol. Chem., Vol. 278, Issue 37, 35531-35541, September 12, 2003

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The Structural Evolution of a P2Y-like G-protein-coupled Receptor^*,

Angela Schulz and Torsten Schöneberg 

From the Institute of Pharmacology, Medical Faculty, Free University Berlin, 14195 Berlin, Germany and the Institute of Biochemistry, Department of Molecular Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany

Based on the now available crystallographic data of the G-protein-coupled receptor (GPCR) prototype rhodopsin, many studies have been undertaken to build or verify models of other GPCRs. Here, we mined evolution as an additional source of structural information that may guide GPCR model generation as well as mutagenesis studies. The sequence information of 61 cloned orthologs of a P2Y-like receptor (GPR34) enabled us to identify motifs and residues that are important for maintaining the receptor function. The sequence data were compared with available sequences of 77 rhodopsin orthologs. Under a negative selection mode, only 17% of amino acid residues were preserved during 450 million years of GPR34 evolution. On the contrary, in rhodopsin evolution 43% residues were absolutely conserved between fish and mammals. Despite major differences in their structural conservation, a comparison of structural data suggests that the global arrangement of the transmembrane core of GPR34 orthologs is similar to rhodopsin. The evolutionary approach was further applied to functionally analyze the relevance of common scaffold residues and motifs found in most of the rhodopsin-like GPCRs. Our analysis indicates that, in contrast to other GPCRs, maintaining the unique function of rhodopsin requires a more stringent network of relevant intramolecular constrains.

Received for publication, April 1, 2003 , and in revised form, June 23, 2003.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY241066–AY241131.

^* This work was supported by the Deutsche Forschungsgemeinschaft, Sonnenfeld-Stiftung, and Fonds der Chemischen Industrie. 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 Tables S1–S3 and supplemental Figs. S1–S3.

To whom correspondence should be addressed: Inst. of Biochemistry, Dept. of Molecular Biochemistry (Interim at the Max Planck Inst. for Evolutionary Anthropology), Medical Faculty, University of Leipzig, Deutscher Platz 6, 04103 Leipzig, Germany. Tel.: 49-341-3550-850; Fax: 49-341-3550-855; E-mail: schoberg{at}medizin.uni-leipzig.de.

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