Structure of the integral membrane domain of the GLP1 receptor

A three‐dimensional (3D) model of the integral membrane domain of the GLP1 receptor, a member of the secretin receptor family of the G‐protein‐coupled receptor superfamily is proposed. The probable arrangement of the seven helices in this receptor was deduced from a detailed analysis of all the sequences in the secretin receptor family. The analysis includes: 1) identifying the transmembrane helices, 2) charge distribution analysis to estimate to which extent the transmembrane helices are buried, 3) Fourier transform analysis of different property profiles within the transmembrane helices to determine the orientation of exposed and buried faces of the helices, 4) alignment of sequences with those of the rhodopsin‐like family using the novel “cold spot” method reported herein, 5) determination of lengths of transmembrane helices and their connecting loops and the constraints these impose on packing, tilting and organization, 6) incorporation of mutagenesis and ligand specificity data. We find that there is a close similarity between the structural properties of receptors of the secretin family and those of the rhodopsin‐like family as typified by the frog rhodopsin structure recently solved by electron cryomicroscopy. Proteins 1999;35:375–386. © 1999 Wiley‐Liss, Inc.

[1]  M. Schiffer,et al.  Use of helical wheels to represent the structures of proteins and to identify segments with helical potential. , 1967, Biophysical journal.

[2]  G. Rummel,et al.  Crystal structures explain functional properties of two E. coli porins , 1992, Nature.

[3]  A. Scheer,et al.  Constitutively active mutants of the alpha 1B‐adrenergic receptor: role of highly conserved polar amino acids in receptor activation. , 1996, The EMBO journal.

[4]  David Eisenberg,et al.  The helical hydrophobic moment: a measure of the amphiphilicity of a helix , 1982, Nature.

[5]  C. DeLisi,et al.  Hydrophobicity scales and computational techniques for detecting amphipathic structures in proteins. , 1987, Journal of molecular biology.

[6]  L. Cardle,et al.  Identification of important functional environs in protein tertiary structures from the analysis of residue variation in 3-D: application to cytochromes c and carboxypeptidases A and B. , 1994, Protein engineering.

[7]  William R. Taylor,et al.  Motif-Biased Protein Sequence Alignment , 1994, J. Comput. Biol..

[8]  John P. Overington,et al.  Environment‐specific amino acid substitution tables: Tertiary templates and prediction of protein folds , 1992, Protein science : a publication of the Protein Society.

[9]  J. Vilardaga,et al.  Lysine 173 residue within the first exoloop of rat secretin receptor is involved in carboxylate moiety recognition of Asp 3 in secretin. , 1996, Biochemical and biophysical research communications.

[10]  John P. Overington,et al.  Modeling α‐helical transmembrane domains: The calculation and use of substitution tables for lipid‐facing residues , 1993, Protein science : a publication of the Protein Society.

[11]  H. Khorana,et al.  Assembly of functional rhodopsin requires a disulfide bond between cysteine residues 110 and 187. , 1990, The Journal of biological chemistry.

[12]  W R Taylor,et al.  Deriving an amino acid distance matrix. , 1993, Journal of theoretical biology.

[13]  J. Baldwin,et al.  An alpha-carbon template for the transmembrane helices in the rhodopsin family of G-protein-coupled receptors. , 1997, Journal of molecular biology.

[14]  R. Iyengar,et al.  The hepatic glucagon receptor. Solubilization, characterization, and development of an affinity adsorption assay for the soluble receptor. , 1984, The Journal of biological chemistry.

[15]  G Vriend,et al.  The interaction of class B G protein-coupled receptors with their hormones. , 1998, Receptors & channels.

[16]  J. Fahrenkrug,et al.  Proposed arrangement of the seven transmembrane helices in the secretin receptor family. , 1998, Receptors & channels.

[17]  T. Schwartz,et al.  Constitutive activity of glucagon receptor mutants. , 1998, Molecular endocrinology.

[18]  T. Schwartz,et al.  Conversion of antagonist-binding site to metal-ion site in the tachykinin NK-1 receptor , 1995, Nature.

[19]  T O Yeates,et al.  Structure of the reaction center from Rhodobacter sphaeroides R-26 and 2.4.1: symmetry relations and sequence comparisons between different species. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[20]  H. Jüppner,et al.  A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. , 1995, Science.

[21]  Gebhard F. X. Schertler,et al.  Arrangement of rhodopsin transmembrane α-helices , 1997, Nature.

[22]  J. Baldwin.  The probable arrangement of the helices in G protein‐coupled receptors. , 1993, The EMBO journal.

[23]  M. Caron,et al.  Role of extracellular disulfide-bonded cysteines in the ligand binding function of the beta 2-adrenergic receptor. , 1990, Biochemistry.

[24]  H. Jüppner,et al.  Determinants of [Arg2]PTH-(1-34) binding and signaling in the transmembrane region of the parathyroid hormone receptor. , 1994, Endocrinology.

[25]  G Vriend,et al.  WHAT IF: a molecular modeling and drug design program. , 1990, Journal of molecular graphics.

[26]  E. Hulme,et al.  Muscarinic acetylcholine receptors. Peptide sequencing identifies residues involved in antagonist binding and disulfide bond formation. , 1990, The Journal of biological chemistry.

[27]  John P. Overington,et al.  The prediction and orientation of alpha-helices from sequence alignments: the combined use of environment-dependent substitution tables, Fourier transform methods and helix capping rules. , 1994, Protein engineering.

[28]  G Vriend,et al.  A common step for signal transduction in G protein-coupled receptors. , 1994, Trends in pharmacological sciences.

[29]  R M Stroud,et al.  Amphipathic analysis and possible formation of the ion channel in an acetylcholine receptor. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[30]  H. Khorana,et al.  Requirement of Rigid-Body Motion of Transmembrane Helices for Light Activation of Rhodopsin , 1996, Science.

[31]  C. Deber,et al.  Peptides in membranes: Helicity and hydrophobicity , 1995, Biopolymers.

[32]  D. Eisenberg,et al.  A method to identify protein sequences that fold into a known three-dimensional structure. , 1991, Science.

[33]  John P. Overington,et al.  Tertiary structural constraints on protein evolutionary diversity: templates, key residues and structure prediction , 1990, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[34]  D. Donnelly,et al.  Predicting the point at which transmembrane helices protrude from the bilayer: a model of the antenna complexes from photosynthetic bacteria. , 1993, Protein engineering.

[35]  D. Eisenberg,et al.  The hydrophobic moment detects periodicity in protein hydrophobicity. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Michel Bouvier,et al.  A Peptide Derived from a β2-Adrenergic Receptor Transmembrane Domain Inhibits Both Receptor Dimerization and Activation* , 1996, The Journal of Biological Chemistry.

[37]  G. Schulz,et al.  Molecular architecture and electrostatic properties of a bacterial porin. , 1991, Science.

[38]  B. Rost,et al.  Transmembrane helices predicted at 95% accuracy , 1995, Protein science : a publication of the Protein Society.

[39]  D. Donnelly.  The arrangement of the transmembrane helices in the secretin receptor family of G‐protein‐coupled receptors , 1997, FEBS letters.

[40]  A. Helenius,et al.  Glycan-dependent and -independent Association of Vesicular Stomatitis Virus G Protein with Calnexin* , 1996, The Journal of Biological Chemistry.

[41]  T. A. Jones,et al.  Using known substructures in protein model building and crystallography. , 1986, The EMBO journal.

[42]  R. Henderson,et al.  Model for the structure of bacteriorhodopsin based on high-resolution electron cryo-microscopy. , 1990, Journal of molecular biology.

[43]  C. Deber,et al.  A measure of helical propensity for amino acids in membrane environments , 1994, Nature Structural Biology.

[44]  T L Blundell,et al.  The evolution and structure of aminergic G protein-coupled receptors. , 1994, Receptors & channels.

[45]  M. O. Dayhoff,et al.  Atlas of protein sequence and structure , 1965 .

[46]  Heijne,et al.  Membrane protein topology: effects of delta mu H+ on the translocation of charged residues explain the ‘positive inside’ rule. , 1994, The EMBO journal.

[47]  J U Bowie,et al.  Helix packing in membrane proteins. , 1997, Journal of molecular biology.

[48]  F. Cohen,et al.  An evolutionary trace method defines binding surfaces common to protein families. , 1996, Journal of molecular biology.

[49]  C. Sander,et al.  Database of homology‐derived protein structures and the structural meaning of sequence alignment , 1991, Proteins.

[50]  J. Ballesteros,et al.  [19] Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors , 1995 .

[51]  C Higgs,et al.  Domain swapping in G-protein coupled receptor dimers. , 1998, Protein engineering.

[52]  A. Valencia,et al.  Correlated mutations contain information about protein-protein interaction. , 1997, Journal of molecular biology.

[53]  R. Nissenson,et al.  Mutations of neighboring polar residues on the second transmembrane helix disrupt signaling by the parathyroid hormone receptor. , 1996, Molecular endocrinology.