title: Using ortholog sequence data to predict the functional relevance of mutations in G-protein-coupled receptors.
abstract: Evaluating the functional relevance of naturally occurring gene variants usually requires experimental testing or is even impossible because of the lack of appropriate functional assays. Here we have analyzed whether comparative sequence data from orthologs are suitable to predict the functional relevance of mutations in a model protein, a G-protein-coupled receptor for ADP (P2Y(12)). The functional effect of every possible substitution at each amino acid position within a portion of P2Y(12) (1254 mutants) was individually determined. Sequence analysis of >70 P2Y(12) vertebrate orthologs revealed that this amino acid variability ensuring proper receptor function in vivo highly correlates (>90%) with the in vitro experimental data. Therefore, ortholog sequence data are helpful to predict the functional relevance of individual positions and mutations for P2Y(12). It is likely that similar conclusions may be extended for other GPCRs and conserved proteins as well.
authors.affiliation: Molecular Biochemistry, Institute of Biochemistry, Medical Faculty, University of Leipzig, Leipzig, Germany.
authors.forename: Maxi
authors.initials: M
authors.lastname: Cöster
authors.forename: Doreen
authors.initials: D
authors.lastname: Wittkopf
authors.forename: Annika
authors.initials: A
authors.lastname: Kreuchwig
authors.forename: Gunnar
authors.initials: G
authors.lastname: Kleinau
authors.forename: Doreen
authors.initials: D
authors.lastname: Thor
authors.forename: Gerd
authors.initials: G
authors.lastname: Krause
authors.forename: Torsten
authors.initials: T
authors.lastname: Schöneberg
mesh_terms: D000595:Amino Acid Sequence; D019143:Evolution, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D058925:Receptors, Purinergic P2Y12 / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D017386:Sequence Homology, Amino Acid
chemical_list: D058925:Receptors, Purinergic P2Y12