The study of G‐protein coupled receptor oligomerization with computational modeling and bioinformatics

To achieve a structural context for the analysis of G‐protein coupled receptor (GPCR) oligomers, molecular modeling must be used to predict the corresponding interaction interfaces. The task is complicated by the paucity of detailed structural data at atomic resolution, and the large number of possible modes in which the bundles of seven transmembrane (TM) segments of the interacting GPCR monomers can be packed together into dimers and/or higher‐order oligomers. Approaches and tools offered by bioinformatics can be used to reduce the complexity of this task and, combined with computational modeling, can serve to yield testable predictions for the structural properties of oligomers. Most of the bioinformatics methods take advantage of the evolutionary relation that exists among GPCRs, as expressed in their sequences and measurable in the common elements of their structural and functional features. These common elements are responsible for the presence of detectable patterns of motifs and correlated mutations evident from the alignment of the sequences of these complex biological systems. The decoding of these patterns in terms of structural and functional determinants can provide indications about the most likely interfaces of dimerization/oligomerization of GPCRs. We review here the main approaches from bioinformatics, enhanced by computational molecular modeling, that have been used to predict likely interfaces of dimerization/oligomerization of GPCRs, and compare results from their application to rhodopsin‐like GPCRs. A compilation of the most frequently predicted GPCR oligomerization interfaces points to specific regions of TMs 4–6.

[1]  F. Ayala,et al.  ADH evolution and the phylogenetic footprint , 1995, Journal of Molecular Evolution.

[2]  N. Ben-Tal,et al.  ConSurf: an algorithmic tool for the identification of functional regions in proteins by surface mapping of phylogenetic information. , 2001, Journal of molecular biology.

[3]  R A Goldstein,et al.  Using physical-chemistry-based substitution models in phylogenetic analyses of HIV-1 subtypes. , 1999, Molecular biology and evolution.

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

[5]  Orkun S. Soyer,et al.  Dimerization in aminergic G-protein-coupled receptors: application of a hidden-site class model of evolution. , 2003, Biochemistry.

[6]  M. Bouvier,et al.  Roles of G‐protein‐coupled receptor dimerization , 2004, EMBO reports.

[7]  D. Eisenberg,et al.  Three-dimensional cluster analysis identifies interfaces and functional residue clusters in proteins. , 2001, Journal of molecular biology.

[8]  A. Engel,et al.  Atomic-force microscopy: Rhodopsin dimers in native disc membranes , 2003, Nature.

[9]  M. Sternberg,et al.  Prediction of protein-protein interactions by docking methods. , 2002, Current opinion in structural biology.

[10]  A. Engel,et al.  The G protein‐coupled receptor rhodopsin in the native membrane , 2004, FEBS letters.

[11]  Miguel A. Andrade-Navarro,et al.  Classification of protein families and detection of the determinant residues with an improved self-organizing map , 1997, Biological Cybernetics.

[12]  J. Ballesteros,et al.  Structural mimicry in G protein-coupled receptors: implications of the high-resolution structure of rhodopsin for structure-function analysis of rhodopsin-like receptors. , 2001, Molecular pharmacology.

[13]  K. Palczewski,et al.  Crystal Structure of Rhodopsin: A G‐Protein‐Coupled Receptor , 2002, Chembiochem : a European journal of chemical biology.

[14]  M. Caron,et al.  Chimeric alpha 2-,beta 2-adrenergic receptors: delineation of domains involved in effector coupling and ligand binding specificity. , 1988, Science.

[15]  Gerda E Breitwieser,et al.  G protein-coupled receptor oligomerization: implications for G protein activation and cell signaling. , 2004, Circulation research.

[16]  H. Lother,et al.  Involvement of the Amino Terminus of the B2 Receptor in Agonist-induced Receptor Dimerization* , 1999, The Journal of Biological Chemistry.

[17]  Kendall J Blumer,et al.  The Extracellular N-terminal Domain and Transmembrane Domains 1 and 2 Mediate Oligomerization of a Yeast G Protein-coupled Receptor* , 2002, The Journal of Biological Chemistry.

[18]  Marta Filizola,et al.  Prediction of heterodimerization interfaces of G-protein coupled receptors with a new subtractive correlated mutation method. , 2002, Protein engineering.

[19]  H. Akil,et al.  Inhibition of cell surface expression by mutant receptors demonstrates that D2 dopamine receptors exist as oligomers in the cell. , 2000, Molecular pharmacology.

[20]  C. Sander,et al.  A method to predict functional residues in proteins , 1995, Nature Structural Biology.

[21]  Graeme Milligan,et al.  Domain Swapping in the Human Histamine H1 Receptor , 2004, Journal of Pharmacology and Experimental Therapeutics.

[22]  O. Lichtarge,et al.  Evolutionary Trace of G Protein-coupled Receptors Reveals Clusters of Residues That Determine Global and Class-specific Functions* , 2004, Journal of Biological Chemistry.

[23]  Gert Vriend,et al.  A common motif in G-protein-coupled seven transmembrane helix receptors , 1993, J. Comput. Aided Mol. Des..

[24]  Alfonso Valencia,et al.  Comparative Analysis of Different Methods for the Detection of Specificity Regions in Protein Families , 1997, BCEC.

[25]  R A Goldstein,et al.  Context-dependent optimal substitution matrices. , 1995, Protein engineering.

[26]  G. Milligan,et al.  Multiple Interactions between Transmembrane Helices Generate the Oligomeric α1b-Adrenoceptor , 2004, Molecular Pharmacology.

[27]  C. Sander,et al.  Correlated mutations and residue contacts in proteins , 1994, Proteins.

[28]  Olivier Lichtarge,et al.  Evolutionary traces of functional surfaces along G protein signaling pathway. , 2002, Methods in enzymology.

[29]  G Vriend,et al.  Correlated Mutation Analyses on Very Large Sequence Families , 2002, Chembiochem : a European journal of chemical biology.

[30]  O. Lichtarge,et al.  Structural clusters of evolutionary trace residues are statistically significant and common in proteins. , 2002, Journal of molecular biology.

[31]  Alfonso Valencia,et al.  Identification of amino acid residues crucial for chemokine receptor dimerization , 2004, Nature Immunology.

[32]  J. Wess,et al.  Functional rescue of mutant V2 vasopressin receptors causing nephrogenic diabetes insipidus by a co‐expressed receptor polypeptide. , 1996, The EMBO journal.

[33]  T. Schwartz,et al.  Split-receptors in the tachykinin neurokinin-1 system--mutational analysis of intracellular loop 3. , 1998, European journal of biochemistry.

[34]  T. Gudermann,et al.  Functional and structural complexity of signal transduction via G-protein-coupled receptors. , 1997, Annual review of neuroscience.

[35]  G. J. G. Upton,et al.  Spatial data Analysis by Example , 1985 .

[36]  T. Coburn.  Spatial Data Analysis by Example , 1991 .

[37]  Mei Bai,et al.  Dimerization of G-protein-coupled receptors: roles in signal transduction. , 2004, Cellular signalling.

[38]  T. Lybrand,et al.  A peptide agonist acts by occupation of a monomeric G protein-coupled receptor: dual sites of covalent attachment to domains near TM1 and TM7 of the same molecule make biologically significant domain-swapped dimerization unlikely. , 1999, Journal of medicinal chemistry.

[39]  K D Ridge,et al.  Examining Rhodopsin Folding and Assembly through Expression of Polypeptide Fragments (*) , 1996, The Journal of Biological Chemistry.

[40]  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 .

[41]  K Konvicka,et al.  A reciprocal mutation supports helix 2 and helix 7 proximity in the gonadotropin-releasing hormone receptor. , 1994, Molecular pharmacology.

[42]  Sang Joon Kim,et al.  A Mathematical Theory of Communication , 2006 .

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

[44]  R A Goldstein,et al.  Models of natural mutations including site heterogeneity , 1998, Proteins.

[45]  A. Valencia,et al.  Computational methods for the prediction of protein interactions. , 2002, Current opinion in structural biology.

[46]  Claude E. Shannon,et al.  The Mathematical Theory of Communication , 1950 .

[47]  F E Cohen,et al.  Identification of functional surfaces of the zinc binding domains of intracellular receptors. , 1997, Journal of molecular biology.

[48]  Christopher A Reynolds,et al.  Dimerization and Domain Swapping in G-Protein-Coupled Receptors: A Computational Study , 2000, Neuropsychopharmacology.

[49]  Werner Braun,et al.  Exact and efficient analytical calculation of the accessible surface areas and their gradients for macromolecules , 1998, J. Comput. Chem..

[50]  T. Gudermann,et al.  Structural Implication for Receptor Oligomerization from Functional Reconstitution Studies of Mutant V2 Vasopressin Receptors* , 2000, The Journal of Biological Chemistry.

[51]  Georgios G. Gkoutos,et al.  Lipid-facing correlated mutations and dimerization in G-protein coupled receptors. , 2001, Protein engineering.

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

[53]  C. Reynolds,et al.  Simulations on dimeric peptides: evidence for domain swapping in G-protein-coupled receptors? , 1997, Biochemical Society transactions.

[54]  J. S. Dixon,et al.  Evaluation of the CASP2 docking section , 1997, Proteins.

[55]  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.

[56]  Marta Filizola,et al.  Structural models for dimerization of G-protein coupled receptors: the opioid receptor homodimers. , 2002, Biopolymers.

[57]  Graeme Milligan,et al.  Dimers of Class A G Protein-coupled Receptors Function via Agonist-mediated Trans-activation of Associated G Proteins* , 2003, Journal of Biological Chemistry.

[58]  J. Wess,et al.  Coexpression studies with mutant muscarinic/adrenergic receptors provide evidence for intermolecular "cross-talk" between G-protein-linked receptors. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[59]  H Weinstein,et al.  Related Contribution of Specific Helix 2 and 7 Residues to Conformational Activation of the Serotonin 5-HT2A Receptor (*) , 1995, The Journal of Biological Chemistry.

[60]  F. Cohen,et al.  Co-evolution of proteins with their interaction partners. , 2000, Journal of molecular biology.

[61]  B. Roth,et al.  Differential modes of agonist binding to 5-hydroxytryptamine(2A) serotonin receptors revealed by mutation and molecular modeling of conserved residues in transmembrane region 5. , 2000, Molecular pharmacology.

[62]  L Rychlewski,et al.  From fold predictions to function predictions: Automation of functional site conservation analysis for functional genome predictions , 1999, Protein science : a publication of the Protein Society.

[63]  A. Valencia,et al.  In silico two‐hybrid system for the selection of physically interacting protein pairs , 2002, Proteins.

[64]  Graeme Milligan,et al.  G Protein-Coupled Receptor Dimerization: Function and Ligand Pharmacology , 2004, Molecular Pharmacology.

[65]  Laerte Oliveira,et al.  Sequence analysis reveals how G protein–coupled receptors transduce the signal to the G protein , 2003, Proteins.

[66]  Lei Shi,et al.  The Fourth Transmembrane Segment Forms the Interface of the Dopamine D2 Receptor Homodimer* , 2003, The Journal of Biological Chemistry.

[67]  C. E. SHANNON,et al.  A mathematical theory of communication , 1948, MOCO.

[68]  J. Klco,et al.  C5a Receptor Oligomerization , 2003, Journal of Biological Chemistry.

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

[70]  G Vriend,et al.  Receptors coupling to G proteins: Is there a signal behind the sequence? , 2000, Proteins.

[71]  Jie Liu,et al.  Plasma Membrane Localization and Functional Rescue of Truncated Forms of a G Protein-coupled Receptor (*) , 1995, The Journal of Biological Chemistry.

[72]  M. Sternberg,et al.  Prediction of protein secondary structure and active sites using the alignment of homologous sequences. , 1987, Journal of molecular biology.

[73]  C. Higgs,et al.  Evidence for dimerization in the beta(2)-adrenergic receptor from the evolutionary trace method , 1999 .

[74]  C. Reynolds,et al.  A new approach to docking in the beta 2-adrenergic receptor that exploits the domain structure of G-protein-coupled receptors. , 1997, Journal of medicinal chemistry.

[75]  F E Cohen,et al.  Evolutionarily conserved Galphabetagamma binding surfaces support a model of the G protein-receptor complex. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[76]  Geoffrey J. Barton,et al.  Protein sequence alignments: a strategy for the hierarchical analysis of residue conservation , 1993, Comput. Appl. Biosci..

[77]  Paul D. Scott,et al.  Dimerization of G-protein-coupled receptors. , 2001 .

[78]  A. Lesk,et al.  The relation between the divergence of sequence and structure in proteins. , 1986, The EMBO journal.

[79]  Harel Weinstein,et al.  Three-dimensional representations of G protein-coupled receptor structures and mechanisms. , 2002, Methods in enzymology.

[80]  L. Devi,et al.  Dimerization of the delta opioid receptor: implication for a role in receptor internalization. , 1997, The Journal of biological chemistry.

[81]  Krzysztof Palczewski,et al.  Organization of the G Protein-coupled Receptors Rhodopsin and Opsin in Native Membranes* , 2003, Journal of Biological Chemistry.

[82]  Jaak Vilo,et al.  Prediction of the coupling specificity of G protein coupled receptors to their G proteins , 2001, ISMB.

[83]  Jonathan A. Javitch,et al.  Oligomerization Domains of G Protein-Coupled Receptors , 2005 .

[84]  O. Lichtarge,et al.  Evolutionary predictions of binding surfaces and interactions. , 2002, Current opinion in structural biology.

[85]  Itay Mayrose,et al.  Rate4Site: an algorithmic tool for the identification of functional regions in proteins by surface mapping of evolutionary determinants within their homologues , 2002, ISMB.

[86]  A. Valencia,et al.  Improving contact predictions by the combination of correlated mutations and other sources of sequence information. , 1997, Folding & design.

[87]  G Vriend,et al.  A low resolution model for the interaction of G proteins with G protein-coupled receptors. , 1999, Protein engineering.

[88]  A. Valencia,et al.  Automatic methods for predicting functionally important residues. , 2003, Journal of molecular biology.

[89]  J. Wess,et al.  Use of an in situ disulfide cross-linking strategy to map proximities between amino acid residues in transmembrane domains I and VII of the M3 muscarinic acetylcholine receptor. , 2002, Biochemistry.

[90]  Ilya A Vakser,et al.  Strategies for modeling the interactions of transmembrane helices of G protein-coupled receptors by geometric complementarity using the GRAMM computer algorithm. , 2002, Methods in enzymology.