A proposed structure for transmembrane segment 7 of G protein-coupled receptors incorporating an asn-Pro/Asp-Pro motif.
Transmembrane segment (TMS) 7 has been shown to play an important role in the signal transduction function of G-protein-coupled receptors (GPCRs). Although transmembrane segments are most likely to adopt a helical structure, results from a variety of experimental studies involving TMS 7 are inconsistent with it being an ideal alpha-helix. Using results from a search of the structure database and extensive simulated annealing Monte Carlo runs with the new Conformational Memories method, we have identified the conserved (N/D)PxxY region of TMS 7 as the major determinant for deviation of TMS 7 from ideal helicity. The perturbation consists of an Asx turn and a flexible "hinge" region. The Conformational Memories procedure yielded a model structure of TMS 7 which, unlike an ideal alpha-helix, is capable of accommodating all of the experimentally derived geometrical criteria for the interactions of TMS 7 in the transmembrane bundle of GPCRs. In the context of the entire structure of a transmembrane bundle model for the 5HT2a receptor, the specific perturbation of TMS 7 by the NP sequence suggests a structural hypothesis for the pattern of amino acid conservation observed in TMS 1, 2, and 7 of GPCRs. The structure resulting from the incorporation of the (N/D)P motif satisfies fully the H-bonding capabilities of the 100% conserved polar residues in these TMSs, in agreement with results from mutagenesis experiments. The flexibility introduced by the specific structural perturbation produced by the (NP/DP) motif in TMS 7 is proposed to have a significant role in receptor activation.
Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York, New York 10029, USA.
K
K
Konvicka
F
F
Guarnieri
J A
JA
Ballesteros
H
H
Weinstein
D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000502:physiology; D017124:Conserved Sequence; D019992:Databases as Topic; D004151:Dipeptides; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D017433:Protein Structure, Secondary; D044402:Receptor, Serotonin, 5-HT2A; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000502:physiology; D011985:Receptors, Serotonin / Q000737:chemistry* / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry; D016415:Sequence Alignment; D015398:Signal Transduction
D004151:Dipeptides; D010446:Peptide Fragments; D044402:Receptor, Serotonin, 5-HT2A; D011956:Receptors, Cell Surface; D011985:Receptors, Serotonin; D011994:Recombinant Proteins; C113843:asparaginyl-proline; C070752:aspartyl-proline; D019204:GTP-Binding Proteins