Modulation of constitutive activity and signaling bias of the ghrelin receptor by conformational constraint in the second extracellular loop

Journal of Biological Chemistry

Volumn 287, Issue 40, 2012, Pages 33488-33502

  Mokrosin, Jacek ^a,b   Frimurer, Thomas M ^c   Sivertsen, Bjørn ^a,b   Schwartz, Thue W ^a,b   Holsts, Birgitte ^a,b  

^a UNIVERSITY OF COPENHAGEN   (Denmark)

^b Capital Region   (Denmark)

^c University of Copenhagen   (Denmark)

Author keywords

[No Author keywords available]

Indexed keywords

AMINO ACID RESIDUES; C-TERMINAL SEGMENTS; CHARGE-CHARGE INTERACTIONS; CONFORMATIONAL CONSTRAINTS; CYS RESIDUES; EXTRACELLULAR LOOP 2; EXTRACELLULAR LOOPS; GHRELIN RECEPTOR; HELICAL CONFORMATION; LIGAND BINDING; LOOP SEGMENTS; MUTATIONAL ANALYSIS; PHYSICOCHEMICAL PROPERTY; POSITIVELY CHARGED; POTENTIAL PARTNERS; TRANS-MEMBRANE DOMAINS; TRANSMEMBRANE SEGMENTS; WILD TYPES;

ACTIVATION ANALYSIS; AMINO ACIDS; BIOLOGICAL MEMBRANES; METAL IONS;

SIGNALING;

ALANINE; BETA ARRESTIN; GHRELIN RECEPTOR; GLUTAMINE; LYSINE; ZINC ION;

ALPHA HELIX; ARTICLE; CARBOXY TERMINAL SEQUENCE; CELL STRAIN COS7; CONTROLLED STUDY; LIGAND BINDING; MOLECULAR BIOLOGY; MUTATION; PHYSICAL CHEMISTRY; PRIORITY JOURNAL; PROTEIN CONFORMATION; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN STRUCTURE; SERUM RESPONSIVE ELEMENT; SIGNAL TRANSDUCTION; WILD TYPE;

ALANINE; AMINO ACID SEQUENCE; ANIMALS; ARRESTINS; CERCOPITHECUS AETHIOPS; COS CELLS; DNA MUTATIONAL ANALYSIS; HEK293 CELLS; HUMANS; MODELS, BIOLOGICAL; MODELS, MOLECULAR; MOLECULAR SEQUENCE DATA; PROTEIN CONFORMATION; PROTEIN STRUCTURE, SECONDARY; PROTEIN STRUCTURE, TERTIARY; RECEPTORS, G-PROTEIN-COUPLED; RECEPTORS, GHRELIN; SIGNAL TRANSDUCTION;

EID: 84866314090     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M112.383240     Document Type: Article

References (73)

1. Schwartz, T. W., and Holst, B. (2003) in Textbook of Receptor Pharmacology (Foreman, J. C., and Johansen, T., eds) 2nd Ed., pp. 81-110, CRC Press, Boca Raton, FL
2. Lefkowitz, R. J., and Shenoy, S. K. (2005) Transduction of receptor signals by β-arrestins. Science 308, 512-517
3. Rasmussen, S. G., DeVree, B. T., Zou, Y., Kruse, A. C., Chung, K. Y., Kobilka, T. S., Thian, F. S., Chae, P. S., Pardon, E., Calinski, D., Mathiesen, J. M., Shah, S. T., Lyons, J. A., Caffrey, M., Gellman, S. H., Steyaert, J., Skiniotis, G., Weis, W. I., Sunahara, R. K., and Kobilka, B. K. (2011) Crystal structure of the β2 adrenergic receptor-Gs protein complex. Nature 477, 549-555
4. Bockenhauer, S., Fürstenberg, A., Yao, X. J., Kobilka, B. K., and Moerner, W. E. (2011) Conformational dynamics of single G protein-coupled receptors in solution. J. Phys. Chem. B 115, 13328-13338
5. 2 adrenoceptor. Nature 469, 175-180
6. Kobilka, B. K., and Deupi, X. (2007) Conformational complexity of G-protein-coupled receptors. Trends Pharmacol. Sci. 28, 397-406 (Pubitemid 47087966)
7. Nygaard, R., Frimurer, T. M., Holst, B., Rosenkilde, M. M., and Schwartz, T. W. (2009) Ligand binding and micro-switches in 7TM receptor structures. Trends Pharmacol. Sci. 30, 249-259
8. Elling, C. E., Raffetseder, U., Nielsen, S. M., and Schwartz, T. W. (2000) Disulfide bridge engineering in the tachykinin NK1 receptor. Biochemistry 39, 667-675 (Pubitemid 30065035)
9. Wheatley, M., Wootten, D., Conner, M. T., Simms, J., Kendrick, R., Logan, R. T., Poyner, D. R., and Barwell, J. (2012) Lifting the lid on GPCRs: the role of extracellular loops. Br. J. Pharmacol. 165, 1688-1703
10. 1a vasopressin receptor: key residues, conserved throughout a G-protein-coupled receptor family, identified. J. Biol. Chem. 282, 17405-17412
11. Klco, J. M., Wiegand, C. B., Narzinski, K., and Baranski, T. J. (2005) Essential role for the second extracellular loop in C5a receptor activation. Nat. Struct. Mol. Biol. 12, 320-326 (Pubitemid 43093086)
12. Cherezov, V., Rosenbaum, D. M., Hanson, M. A., Rasmussen, S. G., Thian, F. S., Kobilka, T. S., Choi, H. J., Kuhn, P., Weis, W. I., Kobilka, B. K., and Stevens, R. C. (2007) High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor. Science 318, 1258-1265 (Pubitemid 350172884)
13. Bokoch, M. P., Zou, Y., Rasmussen, S. G., Liu, C. W., Nygaard, R., Rosenbaum, D. M., Fung, J. J., Choi, H. J., Thian, F. S., Kobilka, T. S., Puglisi, J. D., Weis, W. I., Pardo, L., Prosser, R. S., Mueller, L., and Kobilka, B. K. (2010) Ligand-specific regulation of the extracellular surface of a G-protein-coupled receptor. Nature 463, 108-112
14. Banères, J. L., Mesnier, D., Martin, A., Joubert, L., Dumuis, A., and Bockaert, J. (2005) Molecular characterization of a purified 5-HT4 receptor: a structural basis for drug efficacy. J. Biol. Chem. 280, 20253-20260 (Pubitemid 40776722)
15. Palczewski, K., Kumasaka, T., Hori, T., Behnke, C. A., Motoshima, H., Fox, B. A., Le Trong, I., Teller, D. C., Okada, T., Stenkamp, R. E., Yamamoto, M., and Miyano, M. (2000) Crystal structure of rhodopsin: a G protein-coupled receptor. Science 289, 739-745 (Pubitemid 30650186)
16. Katritch, V., Cherezov, V., and Stevens, R. C. (2012) Diversity and modularity of G protein-coupled receptor structures. Trends Pharmacol. Sci. 33, 17-27
17. Warne, T., Serrano-Vega, M. J., Baker, J. G., Moukhametzianov, R., Edwards, P. C., Henderson, R., Leslie, A. G., Tate, C. G., and Schertler, G. F. (2008) Structure of a β1-adrenergic G-protein-coupled receptor. Nature 454, 486-491
18. Rasmussen, S. G., Choi, H. J., Rosenbaum, D. M., Kobilka, T. S., Thian, F. S., Edwards, P. C., Burghammer, M., Ratnala, V. R., Sanishvili, R., Fischetti, R. F., Schertler, G. F., Weis, W. I., and Kobilka, B. K. (2007) Crystal structure of the human β2 adrenergic G-protein-coupled receptor. Nature 450, 383-387 (Pubitemid 350126755)
19. Wu, B., Chien, E. Y., Mol, C. D., Fenalti, G., Liu, W., Katritch, V., Abagyan, R., Brooun, A., Wells, P., Bi, F. C., Hamel, D. J., Kuhn, P., Handel, T. M., Cherezov, V., and Stevens, R. C. (2010) Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science 330, 1066-1071
20. Jaakola, V. P., Griffith, M. T., Hanson, M. A., Cherezov, V., Chien, E. Y., Lane, J. R., Ijzerman, A. P., and Stevens, R. C. (2008) The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist. Science 322, 1211-1217
21. Castañeda, T. R., Tong, J., Datta, R., Culler, M., and Tschöp, M. H. (2010) Ghrelin in the regulation of body weight and metabolism. Front. Neuroendocrinol. 31, 44-60
22. Holst, B., Cygankiewicz, A., Jensen, T. H., Ankersen, M., and Schwartz, T. W. (2003) High constitutive signaling of the ghrelin receptor - identification of a potent inverse agonist. Mol. Endocrinol. 17, 2201-2210 (Pubitemid 37352532)
23. Holst, B., Holliday, N. D., Bach, A., Elling, C. E., Cox, H. M., and Schwartz, T. W. (2004) Common structural basis for constitutive activity of the ghrelin receptor family. J. Biol. Chem. 279, 53806-53817 (Pubitemid 40051890)
24. Damian, M., Marie, J., Leyris, J. P., Fehrentz, J. A., Verdié, P., Martinez, J., Banères, J. L., and Mary, S. (2012) High constitutive activity is an intrinsic feature of ghrelin receptor protein: a study with a functional monomeric GHS-R1a receptor reconstituted in lipid discs. J. Biol. Chem. 287, 3630-3641
25. Pantel, J., Legendre, M., Cabrol, S., Hilal, L., Hajaji, Y., Morisset, S., Nivot, S., Vie-Luton, M. P., Grouselle, D., de Kerdanet, M., Kadiri, A., Epelbaum, J., Le Bouc, Y., and Amselem, S. (2006) Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature. J. Clin. Investig. 116, 760-768 (Pubitemid 43326885)
26. Holst, B., and Schwartz, T. (2006) Ghrelin receptor mutations - too little height and too much hunger. J. Clin. Investig. 116, 637-641 (Pubitemid 43326872)
27. Horton, R. M., Hunt, H. D., Ho, S. N., Pullen, J. K., and Pease, L. R. (1989) Engineering hybrid genes without the use of restriction enzymes: gene splicing by overlap extension. Gene 77, 61-68 (Pubitemid 19125654)
28. Holst, B., Mokrosinski, J., Lang, M., Brandt, E., Nygaard, R., Frimurer, T. M., Beck-Sickinger, A. G., and Schwartz, T. W. (2007) Identification of an efficacy switch region in the ghrelin receptor responsible for interchange between agonism and inverse agonism. J. Biol. Chem. 282, 15799-15811 (Pubitemid 47093306)
29. Graham, F. L., and van der Eb, A. J. (1973) Transformation of rat cells by DNA of human adenovirus 5. Virology 54, 536-539
30. Zoffmann, S., Chollet, A., and Galzi, J. L. (2002) Identification of the extracellular loop 2 as the point of interaction between the N terminus of the chemokine MIP-1α and its CCR1 receptor. Mol. Pharmacol. 62, 729-736 (Pubitemid 36329393)
31. Barth, P., Wallner, B., and Baker, D. (2009) Prediction of membrane protein structures with complex topologies using limited constraints. Proc. Natl. Acad. Sci. U.S.A. 106, 1409-1414
32. Barth, P., Schonbrun, J., and Baker, D. (2007) Toward high-resolution prediction and design of transmembrane helical protein structures. Proc. Natl. Acad. Sci. U.S.A. 104, 15682-15687 (Pubitemid 350035360)
33. Yarov-Yarovoy, V., Schonbrun, J., and Baker, D. (2006) Multipass membrane protein structure prediction using Rosetta. Proteins 62, 1010-1025 (Pubitemid 43364164)
34. Canutescu, A. A., and Dunbrack, R. L. (2003) Cyclic coordinate descent: a robotics algorithm for protein loop closure. Protein Sci. 12, 963-972 (Pubitemid 36505431)
35. Wang, C., Bradley, P., and Baker, D. (2007) Protein-protein docking with backbone flexibility. J. Mol. Biol. 373, 503-519 (Pubitemid 47445567)
36. Mandell, D. J., Coutsias, E. A., and Kortemme, T. (2009) Sub-angstrom accuracy in protein loop reconstruction by robotics-inspired conformational sampling. Nat. Methods 6, 551-552
37. Sivertsen, B., Lang, M., Frimurer, T. M., Holliday, N. D., Bach, A., Els, S., Engelstoft, M. S., Petersen, P. S., Madsen, A. N., Schwartz, T. W., Beck- Sickinger, A. G., and Holst, B. (2011) Unique interaction pattern for a functionally biased ghrelin receptor agonist. J. Biol. Chem. 286, 20845-20860
38. Chien, E. Y., Liu, W., Zhao, Q., Katritch, V., Han, G. W., Hanson, M. A., Shi, L., Newman, A. H., Javitch, J. A., Cherezov, V., and Stevens, R. C. (2010) Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Science 330, 1091-1095
39. 2-adrenergic receptor. Proc. Natl. Acad. Sci. U.S.A. 96, 12322-12327
40. Rosenkilde, M. M., David, R., Oerlecke, I., Benned-Jensen, T., Geumann, U., Beck-Sickinger, A. G., and Schwartz, T. W. (2006) Conformational constraining of inactive and active states of a seven transmembrane receptor by metal ion site engineering in the extracellular end of transmembrane segment V. Mol. Pharmacol. 70, 1892-1901 (Pubitemid 44771905)
41. Mirzadegan, T., Benkö, G., Filipek, S., and Palczewski, K. (2003) Sequence analyses of G-protein-coupled receptors: similarities to rhodopsin. Biochemistry 42, 2759-2767 (Pubitemid 36331518)
42. Rosenbaum, D. M., Rasmussen, S. G., and Kobilka, B. K. (2009) The structure and function of G-protein-coupled receptors. Nature 459, 356-363
43. Storjohann, L., Holst, B., and Schwartz, T. W. (2008) A second disulfide bridge from the N-terminal domain to extracellular loop 2 dampens receptor activity in GPR39. Biochemistry 47, 9198-9207
44. Hanson, M. A., Roth, C. B., Jo, E., Griffith, M. T., Scott, F. L., Reinhart, G., Desale, H., Clemons, B., Cahalan, S. M., Schuerer, S. C., Sanna, M. G., Han, G. W., Kuhn, P., Rosen, H., and Stevens, R. C. (2012) Crystal structure of a lipid G protein-coupled receptor. Science 335, 851-855
45. Kruse, A. C., Hu, J., Pan, A. C., Arlow, D. H., Rosenbaum, D. M., Rosemond, E., Green, H. F., Liu, T., Chae, P. S., Dror, R. O., Shaw, D. E., Weis, W. I., Wess, J., and Kobilka, B. K. (2012) Structure and dynamics of the M3 muscarinic acetylcholine receptor. Nature 482, 552-556
46. Wu, H., Wacker, D., Mileni, M., Katritch, V., Han, G. W., Vardy, E., Liu, W., Thompson, A. A., Huang, X. P., Carroll, F. I., Mascarella, S. W., Westkaemper, R. B., Mosier, P. D., Roth, B. L., Cherezov, V., and Stevens, R. C. (2012) Structure of the human κ-opioid receptor in complex with JDTic. Nature 485, 327-332
47. Manglik, A., Kruse, A. C., Kobilka, T. S., Thian, F. S., Mathiesen, J. M., Sunahara, R. K., Pardo, L., Weis, W. I., Kobilka, B. K., and Granier, S. (2012) Crystal structure of the μ-opioid receptor bound to a morphinan antagonist. Nature 485, 321-326
48. Rohl, C. A., Strauss, C. E., Chivian, D., and Baker, D. (2004) Modeling structurally variable regions in homologous proteins with Rosetta. Proteins 55, 656-677 (Pubitemid 38620090)
49. Ahuja, S., Hornak, V., Yan, E. C., Syrett, N., Goncalves, J. A., Hirshfeld, A., Ziliox, M., Sakmar, T. P., Sheves, M., Reeves, P. J., Smith, S. O., and Eilers, M. (2009) Helix movement is coupled to displacement of the second extracellular loop in rhodopsin activation. Nat. Struct. Mol. Biol. 16, 168-175
50. Altenbach, C., Kusnetzow, A. K., Ernst, O. P., Hofmann, K. P., and Hubbell, W. L. (2008) High-resolution distance mapping in rhodopsin reveals the pattern of helix movement due to activation. Proc. Natl. Acad. Sci. U.S.A. 105, 7439-7444 (Pubitemid 351830036)
51. Hubbell, W. L., Altenbach, C., Hubbell, C. M., and Khorana, H. G. (2003) Rhodopsin structure, dynamics, and activation: a perspective from crystallography, site-directed spin labeling, sulfhydryl reactivity, and disulfide cross-linking. Adv. Protein Chem. 63, 243-290 (Pubitemid 36268430)
52. Gether, U. (2000) Uncovering molecular mechanisms involved in activation of G protein-coupled receptors. Endocr. Rev. 21, 90-113
53. Hornak, V., Ahuja, S., Eilers, M., Goncalves, J. A., Sheves, M., Reeves, P. J., and Smith, S. O. (2010) Light activation of rhodopsin: insights from molecular dynamics simulations guided by solid-state NMR distance restraints. J. Mol. Biol. 396, 510-527
54. Xu, F., Wu, H., Katritch, V., Han, G. W., Jacobson, K. A., Gao, Z. G., Cherezov, V., and Stevens, R. C. (2011) Structure of an agonist-bound human A2A adenosine receptor. Science 332, 322-327
55. Scheerer, P., Park, J. H., Hildebrand, P. W., Kim, Y. J., Krauss, N., Choe, H. W., Hofmann, K. P., and Ernst, O. P. (2008) Crystal structure of opsin in its G-protein-interacting conformation. Nature 455, 497-502
56. Elling, C. E., Frimurer, T. M., Gerlach, L. O., Jorgensen, R., Holst, B., and Schwartz, T. W. (2006) Metal ion site engineering indicates a global toggle switch model for seven-transmembrane receptor activation. J. Biol. Chem. 281, 17337-17346
57. Han, S. J., Hamdan, F. F., Kim, S. K., Jacobson, K. A., Bloodworth, L. M., Li, B., and Wess, J. (2005) Identification of an agonist-induced conformational change occurring adjacent to the ligand-binding pocket of the M3 muscarinic acetylcholine receptor. J. Biol. Chem. 280, 34849-34858 (Pubitemid 41504619)
58. Sansuk, K., Deupi, X., Torrecillas, I. R., Jongejan, A., Nijmeijer, S., Bakker, R. A., Pardo, L., and Leurs, R. (2011) A structural insight into the reorientation of transmembrane domains 3 and 5 during family A G protein-coupled receptor activation. Mol. Pharmacol. 79, 262-269
59. Salom, D., Lodowski, D. T., Stenkamp, R. E., Le Trong, I., Golczak, M., Jastrzebska, B., Harris, T., Ballesteros, J. A., and Palczewski, K. (2006) Crystal structure of a photoactivated deprotonated intermediate of rhodopsin. Proc. Natl. Acad. Sci. U.S.A. 103, 16123-16128 (Pubitemid 44715162)
60. Sánchez-Más, J., Hahmann, C., Gerritsen, I., García-Borrón, J. C., and Jiménez-Cervantes, C. (2004) Agonist-independent, high constitutive activity of the human melanocortin 1 receptor. Pigment Cell Res. 17, 386-395
61. Nijenhuis, W. A., Oosterom, J., and Adan, R. A. (2001) AgRP(83-132) acts as an inverse agonist on the human-melanocortin-4 receptor. Mol. Endocrinol. 15, 164-171 (Pubitemid 32156049)
62. Abadji, V., Lucas-Lenard, J. M., Chin, C., and Kendall, D. A. (1999) Involvement of the carboxyl terminus of the third intracellular loop of the cannabinoid CB1 receptor in constitutive activation of Gs. J. Neurochem. 72, 2032-2038 (Pubitemid 29186007)
63. Portier, M., Rinaldi-Carmona, M., Pecceu, F., Combes, T., Poinot-Chazel, C., Calandra, B., Barth, F., le Fur, G., and Casellas, P. (1999) SR 144528, an antagonist for the peripheral cannabinoid receptor that behaves as an inverse agonist. J. Pharmacol. Exp. Ther. 288, 582-589 (Pubitemid 29119668)
64. Lu, Z. L., and Hulme, E. C. (2000) A network of conserved intramolecular contacts defines the off-state of the transmembrane switch mechanism in a seven-transmembrane receptor. J. Biol. Chem. 275, 5682-5686
65. Schwartz, T. W., and Holst, B. (2007) Allosteric enhancers, allosteric agonists and ago-allosteric modulators: where do they bind and how do they act? Trends Pharmacol. Sci. 28, 366-373 (Pubitemid 47087971)
66. Leach, K., Sexton, P. M., and Christopoulos, A. (2007) Allosteric GPCR modulators: taking advantage of permissive receptor pharmacology. Trends Pharmacol. Sci. 28, 382-389 (Pubitemid 47087967)
67. Avlani, V. A., Gregory, K. J., Morton, C. J., Parker, M. W., Sexton, P. M., and Christopoulos, A. (2007) Critical role for the second extracellular loop in the binding of both orthosteric and allosteric G protein-coupled receptor ligands. J. Biol. Chem. 282, 25677-25686 (Pubitemid 47372845)
68. Thiele, S., Steen, A., Jensen, P. C., Mokrosinski, J., Frimurer, T. M., and Rosenkilde, M. M. (2011) Allosteric and orthosteric sites in CC chemokine receptor (CCR5), a chimeric receptor approach. J. Biol. Chem. 286, 37543-37554
69. Macdonald, D., Mierke, D. F., Li, H., Pellegrini, M., Sachais, B., Krause, J. E., Leeman, S. E., and Boyd, N. D. (2001) Photoaffinity labeling of mutant neurokinin-1 receptors reveals additional structural features of the substance P/NK-1 receptor complex. Biochemistry 40, 2530-2539 (Pubitemid 32171727)
70. Couture, L., Remy, J. J., Rabesona, H., Troalen, F., Pajot-Augy, E., Bozon, V., Haertle, T., Bidart, J. M., and Salesse, R. (1996) A defined epitope on the human choriogonadotropin α-subunit interacts with the second extracellular loop of the transmembrane domain of the lutropin/ choriogonadotropin receptor. Eur. J. Biochem. 241, 627-632 (Pubitemid 26356855)
71. Ryu, K., Lee, H., Kim, S., Beauchamp, J., Tung, C. S., Isaacs, N. W., Ji, I., and Ji, T. H. (1998) Modulation of high affinity hormone binding. Human choriogonadotropin binding to the exodomain of the receptor is influenced by exoloop 2 of the receptor. J. Biol. Chem. 273, 6285-6291 (Pubitemid 28144717)
72. Wheatley, M., Simms, J., Hawtin, S. R., Wesley, V. J., Wootten, D., Conner, M., Lawson, Z., Conner, A. C., Baker, A., Cashmore, Y., Kendrick, R., and Parslow, R. A. (2007) Extracellular loops and ligand binding to a subfamily of Family A G-protein-coupled receptors. Biochem. Soc. Trans. 35, 717-720 (Pubitemid 47310352)
73. Wheatley, M., and Hawtin, S. R. (1999) Glycosylation of G-protein-coupled receptors for hormones central to normal reproductive functioning: its occurrence and role. Hum. Reprod. Update 5, 356-364 (Pubitemid 29381281)