A concept for G protein activation by G protein-coupled receptor dimers: the transducin/rhodopsin interface

G protein-coupled receptors (GPCRs) are ubiquitous and essential in modulating virtually all physiological processes. These receptors share a similar structural design consisting of the seven-transmembrane α-helical segments. The active conformations of the receptors are stabilized by an agonist and couple to structurally highly conserved heterotrimeric G proteins. One of the most important unanswered questions is how GPCRs couple to their cognate G proteins. Phototransduction represents an excellent model system for understanding G protein signaling, owing to the high expression of rhodopsin in rod photoreceptors and the multidisciplinary experimental approaches used to study this GPCR. Here, we describe how a G protein (transducin) docks on to an oligomeric GPCR (rhodopsin), revealing structural details of this critical interface in the signal transduction process. This conceptual model takes into account recent structural information on the receptor and G protein, as well as oligomeric states of GPCRs.

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

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

[3]  Lei Shi,et al.  The second extracellular loop of the dopamine D2 receptor lines the binding-site crevice. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

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

[5]  J. Benovic,et al.  Mapping the Arrestin-Receptor Interface , 2004, Journal of Biological Chemistry.

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

[7]  L. Miller,et al.  Heterodimerization of Type A and B Cholecystokinin Receptors Enhance Signaling and Promote Cell Growth* , 2003, Journal of Biological Chemistry.

[8]  K. Blumer,et al.  Oligomerization, Biogenesis, and Signaling Is Promoted by a Glycophorin A-like Dimerization Motif in Transmembrane Domain 1 of a Yeast G Protein-coupled Receptor* , 2003, Journal of Biological Chemistry.

[9]  B. O'dowd,et al.  Homo- and hetero-oligomerization of G protein-coupled receptors. , 2003, Life sciences.

[10]  Krzysztof Palczewski,et al.  The crystallographic model of rhodopsin and its use in studies of other G protein-coupled receptors. , 2003, Annual review of biophysics and biomolecular structure.

[11]  K. Palczewski,et al.  G protein-coupled receptor rhodopsin: a prospectus. , 2003, Annual review of physiology.

[12]  K. Palczewski,et al.  Evolutionary analysis of rhodopsin and cone pigments: connecting the three‐dimensional structure with spectral tuning and signal transfer , 2003, FEBS letters.

[13]  A. Engel,et al.  Biophysics (communication arising): Is rhodopsin dimeric in native retinal rods? , 2003, Nature.

[14]  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.

[15]  H. Rockman,et al.  Dual Inhibition of &bgr;-Adrenergic and Angiotensin II Receptors by a Single Antagonist: A Functional Role for Receptor–Receptor Interaction In Vivo , 2003, Circulation.

[16]  K. Palczewski,et al.  Phototransduction: crystal clear. , 2003, Trends in biochemical sciences.

[17]  V. Slepak,et al.  Light-Mediated Activation of Rac-1 in Photoreceptor Outer Segments , 2003, Current Biology.

[18]  M. Elliott,et al.  Cholesterol-dependent association of caveolin-1 with the transducin alpha subunit in bovine photoreceptor rod outer segments: disruption by cyclodextrin and guanosine 5'-O-(3-thiotriphosphate). , 2003, Biochemistry.

[19]  Joseph Parello,et al.  Structure-based analysis of GPCR function: evidence for a novel pentameric assembly between the dimeric leukotriene B4 receptor BLT1 and the G-protein. , 2003, Journal of molecular biology.

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

[21]  R. Lefkowitz,et al.  Keeping G Proteins at Bay: A Complex Between G Protein-Coupled Receptor Kinase 2 and Gßγ , 2003, Science.

[22]  Krzysztof Palczewski,et al.  Sequence analyses of G-protein-coupled receptors: similarities to rhodopsin. , 2003, Biochemistry.

[23]  L. Fagni,et al.  Mont Sainte‐Odile: a sanctuary for GPCRs , 2003 .

[24]  Krzysztof Palczewski,et al.  Role of the conserved NPxxY(x)5,6F motif in the rhodopsin ground state and during activation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

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

[26]  Caterina Bissantz,et al.  Conformational Changes of G Protein‐Coupled Receptors During Their Activation by Agonist Binding , 2003, Journal of receptor and signal transduction research.

[27]  Susan R. George,et al.  G-Protein-coupled receptor oligomerization and its potential for drug discovery , 2002, Nature Reviews Drug Discovery.

[28]  V. Slepak,et al.  Signal-Dependent Translocation of Transducin, RGS9-1-Gβ5L Complex, and Arrestin to Detergent-Resistant Membrane Rafts in Photoreceptors , 2002, Current Biology.

[29]  C. Brenner,et al.  Scaffolding functions of arrestin-2 revealed by crystal structure and mutagenesis. , 2002, Biochemistry.

[30]  G. Marshall,et al.  Rhodopsin-transducin interface: studies with conformationally constrained peptides. , 2001, Biophysical journal.

[31]  L. Devi,et al.  G-protein-coupled receptor dimerization: modulation of receptor function. , 2001, Pharmacology & therapeutics.

[32]  H. Lother,et al.  The Angiotensin II AT2 Receptor Is an AT1Receptor Antagonist* , 2001, The Journal of Biological Chemistry.

[33]  H. Lother,et al.  Increased AT1 receptor heterodimers in preeclampsia mediate enhanced angiotensin II responsiveness , 2001, Nature Medicine.

[34]  K. Palczewski,et al.  Crystal structure of rhodopsin: implications for vision and beyond. , 2001, Current opinion in structural biology.

[35]  D C Teller,et al.  Advances in determination of a high-resolution three-dimensional structure of rhodopsin, a model of G-protein-coupled receptors (GPCRs). , 2001, Biochemistry.

[36]  M. Klein,et al.  Structural properties of a highly polyunsaturated lipid bilayer from molecular dynamics simulations. , 2001, Biophysical journal.

[37]  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.

[38]  Han Liu,et al.  Light- and Guanosine 5′-3-O-(Thio)triphosphate-sensitive Localization of a G Protein and Its Effector on Detergent-resistant Membrane Rafts in Rod Photoreceptor Outer Segments* , 2001, The Journal of Biological Chemistry.

[39]  Lakshmi A. Devi,et al.  G protein coupled receptor dimerization: implications in modulating receptor function , 2001, Journal of Molecular Medicine.

[40]  E. Meng,et al.  Mutant G protein α subunit activated by Gβγ: A model for receptor activation? , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[41]  P. D. Calvert,et al.  Membrane protein diffusion sets the speed of rod phototransduction , 2001, Nature.

[42]  K. Palczewski,et al.  Activation of rhodopsin: new insights from structural and biochemical studies. , 2001, Trends in biochemical sciences.

[43]  H. Khorana,et al.  Mapping of contact sites in complex formation between light-activated rhodopsin and transducin by covalent crosslinking: Use of a chemically preactivated reagent , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[44]  H. Khorana,et al.  Mapping of contact sites in complex formation between transducin and light-activated rhodopsin by covalent crosslinking: Use of a photoactivatable reagent , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[45]  G. Milligan,et al.  Oligomerisation of G-protein-coupled receptors. , 2001, Journal of cell science.

[46]  H. Lother,et al.  AT1-receptor heterodimers show enhanced G-protein activation and altered receptor sequestration , 2000, Nature.

[47]  K. Palczewski,et al.  Crystal structure of rhodopsin: A G protein-coupled receptor. , 2000, Science.

[48]  S. Pasquaré,et al.  Lipid metabolism in vertebrate retinal rod outer segments. , 2000, Progress in lipid research.

[49]  U. Gether.  Uncovering molecular mechanisms involved in activation of G protein-coupled receptors. , 2000, Endocrine reviews.

[50]  P. Henklein,et al.  Mutation of the Fourth Cytoplasmic Loop of Rhodopsin Affects Binding of Transducin and Peptides Derived from the Carboxyl-terminal Sequences of Transducin α and γ Subunits* , 2000, The Journal of Biological Chemistry.

[51]  T. Sakmar,et al.  The Amino Terminus of the Fourth Cytoplasmic Loop of Rhodopsin Modulates Rhodopsin-Transducin Interaction* , 2000, The Journal of Biological Chemistry.

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

[53]  S. Sprang,et al.  Structure of Giα1·GppNHp, Autoinhibition in a Gα Protein-Substrate Complex* , 1999, The Journal of Biological Chemistry.

[54]  P. Sigler,et al.  A Model for Arrestin’s Regulation: The 2.8 Å Crystal Structure of Visual Arrestin , 1999, Cell.

[55]  J. Wess,et al.  Functional Characterization of a Series of Mutant G Protein αq Subunits Displaying Promiscuous Receptor Coupling Properties* , 1998, The Journal of Biological Chemistry.

[56]  H. Bourne,et al.  G-protein diseases furnish a model for the turn-on switch , 1998, Nature.

[57]  G R Marshall,et al.  Light-activated rhodopsin induces structural binding motif in G protein alpha subunit. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[58]  G. Büldt,et al.  X-ray crystal structure of arrestin from bovine rod outer segments , 1998, Nature.

[59]  Heidi E. Hamm,et al.  The Many Faces of G Protein Signaling* , 1998, The Journal of Biological Chemistry.

[60]  S R Sprang,et al.  Crystal structure of the catalytic domains of adenylyl cyclase in a complex with Gsalpha.GTPgammaS. , 1997, Science.

[61]  S. Karnik,et al.  Transducin-α C-terminal Peptide Binding Site Consists of C-D and E-F Loops of Rhodopsin* , 1997, The Journal of Biological Chemistry.

[62]  K. Palczewski,et al.  Turned on by Ca2+! The physiology and pathology of Ca2+-binding proteins in the retina , 1996, Trends in Neurosciences.

[63]  S. Sprang,et al.  The crystallographic structure of a G protein heterotrimer , 1996 .

[64]  H. Hamm,et al.  Heterotrimeric G proteins. , 1996, Current opinion in cell biology.

[65]  H. Hamm,et al.  The 2.0 Å crystal structure of a heterotrimeric G protein , 1996, Nature.

[66]  H. Hamm,et al.  Crystal structure of a G-protein βγ dimer at 2.1 Å resolution , 1996, Nature.

[67]  Andrew Bohm,et al.  Crystal structure of a GA protein βγdimer at 2.1 Å resolution , 1996, Nature.

[68]  D. Baylor,et al.  How photons start vision. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[69]  S. Sprang,et al.  The structure of the G protein heterotrimer Giα1 β 1 γ 2 , 1995, Cell.

[70]  M. Rodbell,et al.  Signal transduction: evolution of an idea. , 1995, Environmental health perspectives.

[71]  H. Hamm,et al.  GTPase mechanism of Gproteins from the 1.7-Å crystal structure of transducin α - GDP AIF−4 , 1994, Nature.

[72]  S. Sprang,et al.  Mechanism of GTP hydrolysis by G-protein alpha subunits. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[73]  S. Sprang,et al.  Structures of active conformations of Gi alpha 1 and the mechanism of GTP hydrolysis. , 1994, Science.

[74]  K. Palczewski.  Structure and functions of arrestins , 1994, Protein science : a publication of the Protein Society.

[75]  Heidi E. Hamm,et al.  Structural determinants for activation of the α-subunit of a heterotrimeric G protein , 1994, Nature.

[76]  H. Hamm.  Molecular interactions between the photoreceptor G protein and rhodopsin , 1991, Cellular and Molecular Neurobiology.

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

[78]  W. Schlegel,et al.  Activation of adenylate cyclase in hepatic membranes involves interactions of the catalytic unit with multimeric complexes of regulatory proteins. , 1979, The Journal of biological chemistry.

[79]  E. Dratz,et al.  A reinvestigation of the fatty acid content of bovine, rat and frog retinal rod outer segments. , 1979, Experimental eye research.

[80]  G. Wald,et al.  THE VISUAL CELLS AND VISUAL PIGMENT OF THE MUDPUPPY, NECTURUS , 1963, The Journal of cell biology.

[81]  H. Saibil,et al.  Biophysics: is rhodopsin dimeric in native retinal rods? , 2003, Nature.

[82]  L. Fagni,et al.  meeting report Mont Sainte-Odile: a sanctuary for GPCRs Conference on Signal Transduction of G-Protein-Coupled Receptors , 2003 .

[83]  J. Cherfils,et al.  Activation of G-protein Ga subunits by receptors through GaG and GaG? interactions , 2003 .

[84]  Michel Bouvier,et al.  Dimerization: an emerging concept for G protein-coupled receptor ontogeny and function. , 2002, Annual review of pharmacology and toxicology.