GGIP: Structure and sequence‐based GPCR–GPCR interaction pair predictor

G Protein‐Coupled Receptors (GPCRs) are important pharmaceutical targets. More than 30% of currently marketed pharmaceutical medicines target GPCRs. Numerous studies have reported that GPCRs function not only as monomers but also as homo‐ or hetero‐dimers or higher‐order molecular complexes. Many GPCRs exert a wide variety of molecular functions by forming specific combinations of GPCR subtypes. In addition, some GPCRs are reportedly associated with diseases. GPCR oligomerization is now recognized as an important event in various biological phenomena, and many researchers are investigating this subject. We have developed a support vector machine (SVM)‐based method to predict interacting pairs for GPCR oligomerization, by integrating the structure and sequence information of GPCRs. The performance of our method was evaluated by the Receiver Operating Characteristic (ROC) curve. The corresponding area under the curve was 0.938. As far as we know, this is the only prediction method for interacting pairs among GPCRs. Our method could accelerate the analyses of these interactions, and contribute to the elucidation of the global structures of the GPCR networks in membranes. Proteins 2016; 84:1224–1233. © 2016 Wiley Periodicals, Inc.

[1]  Dániel Kozma,et al.  PDBTM: Protein Data Bank of transmembrane proteins after 8 years , 2012, Nucleic Acids Res..

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

[3]  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.

[4]  Amitabha Chattopadhyay,et al.  GPCRs: Lipid-Dependent Membrane Receptors That Act as Drug Targets , 2014 .

[5]  Martin J. Lohse,et al.  G Protein–Coupled Receptor Oligomerization Revisited: Functional and Pharmacological Perspectives , 2014, Pharmacological Reviews.

[6]  S. Mennerick,et al.  Covalent and noncovalent interactions mediate metabotropic glutamate receptor mGlu5 dimerization. , 2001, Molecular pharmacology.

[7]  Y. Z. Chen,et al.  Protein function classification via support vector machine approach. , 2003, Mathematical biosciences.

[8]  Nello Cristianini,et al.  Support vector machine classification and validation of cancer tissue samples using microarray expression data , 2000, Bioinform..

[9]  Lakshmi A. Devi,et al.  G-protein-coupled receptor heterodimerization modulates receptor function , 1999, Nature.

[10]  Akihiro Kusumi,et al.  Single-molecule imaging revealed dynamic GPCR dimerization. , 2014, Current opinion in cell biology.

[11]  A. Kuliopulos,et al.  and Development G-protein-coupled Receptor Drug Intracellular Pepducins : New Insights into Turning Receptors On and Off with Minireviews , 2012 .

[12]  B. O'dowd,et al.  Oligomerization of mu- and delta-opioid receptors. Generation of novel functional properties. , 2000, The Journal of biological chemistry.

[13]  M S Waterman,et al.  Identification of common molecular subsequences. , 1981, Journal of molecular biology.

[14]  Yusuke Nakamura,et al.  The neuromedin U-growth hormone secretagogue receptor 1b/neurotensin receptor 1 oncogenic signaling pathway as a therapeutic target for lung cancer. , 2006, Cancer research.

[15]  Philippe Delagrange,et al.  The orphan GPR50 receptor specifically inhibits MT1 melatonin receptor function through heterodimerization , 2006, The EMBO journal.

[16]  Joanna L. Sharman,et al.  IUPHAR-DB: updated database content and new features , 2012, Nucleic Acids Res..

[17]  K. Chou,et al.  Protein subcellular location prediction. , 1999, Protein engineering.

[18]  Graeme Milligan,et al.  The role of dimerisation in the cellular trafficking of G-protein-coupled receptors. , 2010, Current opinion in pharmacology.

[19]  Alessandro Senes,et al.  The Cα—H⋅⋅⋅O hydrogen bond: A determinant of stability and specificity in transmembrane helix interactions , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[20]  William Stafford Noble,et al.  Kernel methods for predicting protein-protein interactions , 2005, ISMB.

[21]  Yukimitsu Yabuki,et al.  GRIFFIN: a system for predicting GPCR–G-protein coupling selectivity using a support vector machine and a hidden Markov model , 2005, Nucleic Acids Res..

[22]  Xiaochun Sun,et al.  Opioid Receptor Homo- and Heterodimerization in Living Cells by Quantitative Bioluminescence Resonance Energy Transfer , 2005, Molecular Pharmacology.

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

[24]  Manfred Schmidt,et al.  Partition coefficients of amino acids and hydrophobic parameters π of their side-chains as measured by thin-layer chromatography☆ , 1981 .

[25]  A. Chattopadhyay,et al.  Cholesterol modulates the dimer interface of the β₂-adrenergic receptor via cholesterol occupancy sites. , 2014, Biophysical journal.

[26]  Nafis Rahman,et al.  Rescue of defective G protein–coupled receptor function in vivo by intermolecular cooperation , 2010, Proceedings of the National Academy of Sciences.

[27]  Wataru Nemoto,et al.  GRIP: A server for predicting interfaces for GPCR oligomerization , 2009, Journal of receptor and signal transduction research.

[28]  Haiyan Tan,et al.  Homo- and hetero-dimerization of LPA/S1P receptors, OGR1 and GPR4. , 2006, Biochimica et biophysica acta.

[29]  S. Coughlin,et al.  Anatomical Profiling of G Protein-Coupled Receptor Expression , 2008, Cell.

[30]  Wataru Nemoto,et al.  Prediction of interfaces for oligomerizations of G‐protein coupled receptors , 2004, Proteins.

[31]  R. Shigemoto,et al.  GABAB-receptor subtypes assemble into functional heteromeric complexes , 1998, Nature.

[32]  Jianyun Huang,et al.  Crystal Structure of Oligomeric β1-Adrenergic G Protein- Coupled Receptors in Ligand-Free Basal State , 2013, Nature Structural &Molecular Biology.

[33]  H. Nakata,et al.  Heteromeric association creates a P2Y-like adenosine receptor , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[34]  D. Engelman,et al.  Glycophorin A dimerization is driven by specific interactions between transmembrane alpha-helices. , 1992, The Journal of biological chemistry.

[35]  Amitabha Chattopadhyay,et al.  Oligomerization of the serotonin(1A) receptor in live cells: a time-resolved fluorescence anisotropy approach. , 2011, The journal of physical chemistry. B.

[36]  Sergi Ferré,et al.  GPCR homomers and heteromers: a better choice as targets for drug development than GPCR monomers? , 2009, Pharmacology & therapeutics.

[37]  Ashkan Golshani,et al.  Computational methods for predicting protein-protein interactions. , 2008, Advances in biochemical engineering/biotechnology.

[38]  Jens Meiler,et al.  Structure of a Class C GPCR Metabotropic Glutamate Receptor 1 Bound to an Allosteric Modulator , 2014, Science.

[39]  Lakshmi A. Devi,et al.  Heterodimerization of μ and δ Opioid Receptors: A Role in Opiate Synergy , 2000, The Journal of Neuroscience.

[40]  Lakshmi A Devi,et al.  AT1R–CB1R heteromerization reveals a new mechanism for the pathogenic properties of angiotensin II , 2011, The EMBO journal.

[41]  G. Rose,et al.  Hydrogen bonding, hydrophobicity, packing, and protein folding. , 1993, Annual review of biophysics and biomolecular structure.

[42]  P. Seeman,et al.  A Transmembrane Domain-derived Peptide Inhibits D1 Dopamine Receptor Function without Affecting Receptor Oligomerization* , 1998, The Journal of Biological Chemistry.

[43]  Wataru Nemoto,et al.  Membrane Interactive α-Helices in GPCRs as a Novel Drug Target , 2006 .

[44]  Eric Trinquet,et al.  A new approach to analyze cell surface protein complexes reveals specific heterodimeric metabotropic glutamate receptors , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[45]  Wataru Nemoto,et al.  Membrane interactive alpha-helices in GPCRs as a novel drug target. , 2006, Current protein & peptide science.

[46]  D. Engelman,et al.  Sequence specificity in the dimerization of transmembrane alpha-helices. , 1992, Biochemistry.

[47]  S. Nakanishi,et al.  Cryptic dimer interface and domain organization of the extracellular region of metabotropic glutamate receptor subtype 1. , 2000, The Journal of biological chemistry.

[48]  Lakshmi A Devi,et al.  Opioids and Their Complicated Receptor Complexes , 2000, Neuropsychopharmacology.

[49]  Jordi Ortiz,et al.  Circadian-Related Heteromerization of Adrenergic and Dopamine D4 Receptors Modulates Melatonin Synthesis and Release in the Pineal Gland , 2012, PLoS biology.

[50]  S. Seshagiri,et al.  The emerging mutational landscape of G proteins and G-protein-coupled receptors in cancer , 2013, Nature Reviews Cancer.

[51]  Kuo-Chen Chou,et al.  Prediction of Protein Structural Classes by Support Vector Machines , 2002, Comput. Chem..

[52]  R. Maki,et al.  Dimerization of the melanocortin 4 receptor: A study using bioluminescence resonance energy transfer , 2006, Peptides.

[53]  R. Abagyan,et al.  Structures of the CXCR4 Chemokine GPCR with Small-Molecule and Cyclic Peptide Antagonists , 2010, Science.

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

[55]  Chongguang Chen,et al.  Heterodimerization and cross-desensitization between the mu-opioid receptor and the chemokine CCR5 receptor. , 2004, European journal of pharmacology.

[56]  R. Doolittle,et al.  A simple method for displaying the hydropathic character of a protein. , 1982, Journal of molecular biology.

[57]  G. Marek,et al.  Heterocomplex formation of 5-HT2A-mGlu2 and its relevance for cellular signaling cascades , 2012, Neuropharmacology.

[58]  Carlos G Dotti,et al.  Brain cholesterol in normal and pathological aging. , 2010, Biochimica et biophysica acta.

[59]  George Khelashvili,et al.  GPCR-OKB: the G Protein Coupled Receptor Oligomer Knowledge Base , 2010, Bioinform..

[60]  U. Kumar,et al.  Agonist-dependent Dissociation of Human Somatostatin Receptor 2 Dimers , 2004, Journal of Biological Chemistry.

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

[62]  Lakshmi A Devi,et al.  Disease-specific heteromerization of G-protein-coupled receptors that target drugs of abuse. , 2013, Progress in molecular biology and translational science.

[63]  L F Agnati,et al.  Receptor heteromerization in adenosine A2A receptor signaling , 2003, Neurology.

[64]  Michael Gribskov,et al.  Use of Receiver Operating Characteristic (ROC) Analysis to Evaluate Sequence Matching , 1996, Comput. Chem..

[65]  Graeme Milligan,et al.  Homo- and hetero-oligomeric interactions between G-protein-coupled receptors in living cells monitored by two variants of bioluminescence resonance energy transfer (BRET): hetero-oligomers between receptor subtypes form more efficiently than between less closely related sequences. , 2002, The Biochemical journal.

[66]  Tatiana A. Tatusova,et al.  NCBI Reference Sequences (RefSeq): current status, new features and genome annotation policy , 2011, Nucleic Acids Res..

[67]  S. Wilt,et al.  Heterodimerization of Calcium Sensing Receptors with Metabotropic Glutamate Receptors in Neurons* , 2001, The Journal of Biological Chemistry.

[68]  B. Mouillac,et al.  Oxytocin and vasopressin V1a and V2 receptors form constitutive homo- and heterodimers during biosynthesis. , 2003, Molecular endocrinology.

[69]  S. Schulz,et al.  Allosteric modulation of metabotropic glutamate receptor 5 affects phosphorylation, internalization, and desensitization of the μ-opioid receptor , 2009, Neuropharmacology.

[70]  D. Gehlert,et al.  Co-expression of neuropeptide Y Y1 and Y5 receptors results in heterodimerization and altered functional properties. , 2007, Biochemical pharmacology.

[71]  A. Clayton,et al.  Organization of higher-order oligomers of the serotonin₁(A) receptor explored utilizing homo-FRET in live cells. , 2011, Biophysical journal.

[72]  Marc Parmentier,et al.  GPCRs: Heterodimer-specific signaling. , 2015, Nature chemical biology.

[73]  U. Kumar,et al.  Subtypes of the Somatostatin Receptor Assemble as Functional Homo- and Heterodimers* , 2000, The Journal of Biological Chemistry.

[74]  D. Eisenberg Three-dimensional structure of membrane and surface proteins. , 1984, Annual review of biochemistry.

[75]  W. Meyerhof,et al.  Oligomerization of TAS2R bitter taste receptors. , 2010, Chemical senses.

[76]  Vadim Cherezov,et al.  A specific cholesterol binding site is established by the 2.8 A structure of the human beta2-adrenergic receptor. , 2008, Structure.

[77]  Lakshmi A Devi,et al.  μ opioid and CB1 cannabinoid receptor interactions: reciprocal inhibition of receptor signaling and neuritogenesis , 2006, British journal of pharmacology.

[78]  L. Devi,et al.  Heterodimerization of mu and delta opioid receptors: A role in opiate synergy. , 2000, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[79]  Mark P. Mattson,et al.  Diet‐induced elevations in serum cholesterol are associated with alterations in hippocampal lipid metabolism and increased oxidative stress , 2011, Journal of neurochemistry.

[80]  Michel Bouvier,et al.  Oligomerization of G-protein-coupled transmitter receptors , 2001, Nature Reviews Neuroscience.

[81]  Fu-Yue Zeng,et al.  Molecular Aspects of Muscarinic Receptor Dimerization , 2000, Neuropsychopharmacology.

[82]  Jonathan W. Pillow,et al.  POSTER PRESENTATION Open Access , 2013 .

[83]  Minoru Kanehisa,et al.  Prediction of protein subcellular locations by support vector machines using compositions of amino acids and amino acid pairs , 2003, Bioinform..

[84]  Céline Galés,et al.  Dual agonist occupancy of AT1-R-α2C-AR heterodimers results in atypical Gs-PKA signaling. , 2015, Nature chemical biology.

[85]  Jing Chen,et al.  Heterodimerization of human apelin and kappa opioid receptors: roles in signal transduction. , 2012, Cellular signalling.

[86]  Wataru Nemoto,et al.  GRIPDB - G protein coupled Receptor Interaction Partners DataBase , 2011, Journal of receptor and signal transduction research.