Molecular mechanism of the constitutive activation of the L250Q human melanocortin-4 receptor polymorphism

Chemical Biology and Drug Design

Volumn 67, Issue 3, 2006, Pages 215-229

  Proneth, Bettina ^a   Xiang, Zhimin ^a   Pogozheva, Irina D ^b   Litherland, Sally A ^c   Gorbatyuk, Oleg S ^a   Shaw, Amanda M ^a   Millard, William J ^a   Mosberg, Henry I ^b   Haskell Luevano, Carrie ^a  

^a UNIVERSITY OF FLORIDA   (United States)

^b UNIVERSITY OF MICHIGAN   (United States)

^c UNIVERSITY OF FLORIDA COLLEGE OF MEDICINE   (United States)

Author keywords

Agouti related protein; AGRP; Constitutive activation; G protein coupled receptor; Melanotropin; Obesity; POMC

Indexed keywords

AGOUTI RELATED PROTEIN; CYCLIC AMP; MELANOCORTIN 4 RECEPTOR;

ANIMAL TISSUE; ARTICLE; COMPUTER MODEL; CONTROLLED STUDY; EMBRYO; GENETIC POLYMORPHISM; HUMAN; HUMAN CELL; LEAN BODY WEIGHT; MALE; MOLECULAR MECHANICS; MUTAGENESIS; MUTATION; NONHUMAN; OBESITY; PHENOTYPE; PRIORITY JOURNAL; PROTEIN MODIFICATION; RAT; THEORY;

AGOUTI-RELATED PROTEIN; AMINO ACID SEQUENCE; AMINO ACID SUBSTITUTION; ANIMALS; CELL LINE; CELL MEMBRANE; FEMALE; GENE EXPRESSION REGULATION; GLUTAMINE; HUMANS; HYPOTHALAMUS; LEUCINE; MALE; MOLECULAR SEQUENCE DATA; MUTAGENESIS, SITE-DIRECTED; PEPTIDE FRAGMENTS; POLYMORPHISM, GENETIC; PROTEIN CONFORMATION; RATS; RATS, SPRAGUE-DAWLEY; RECEPTOR, MELANOCORTIN, TYPE 4;

AGOUTI; ANIMALIA;

EID: 33645278983     PISSN: 17470277     EISSN: None     Source Type: Journal    
DOI: 10.1111/j.1747-0285.2006.00362.x     Document Type: Article

References (90)

1. Chhajlani V. Wikberg J.E. 1992 Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA FEBS Lett 309 417 420
2. Mountjoy K.G. Robbins L.S. Mortrud M.T. Cone R.D. 1992 The cloning of a family of genes that encode the melanocortin receptors Science 257 1248 1251
3. Mountjoy K.G. Mortrud M.T. Low M.J. Simerly R.B. Cone R.D. 1994 Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain Mol Endocrinol 8 1298 1308
4. Roselli-Rehfuss L. Mountjoy K.G. Robbins L.S. Mortrud M.T. Low M.J. Tatro J.B. Entwistle M.L. Simerly R.B. Cone R.D. 1993 Identification of a receptor for gamma melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system Proc Natl Acad Sci U S A 90 8856 8860
5. Gantz I. Konda Y. Tashiro T. Shimoto Y. Miwa H. Munzert G. Watson S.J. DelValle J. Yamada T. 1993 Molecular cloning of a novel melanocortin receptor J Biol Chem 268 8246 8250
6. Gantz I. Miwa H. Konda Y. Shimoto Y. Tashiro T. Watson S.J. DelValle J. Yamada T. 1993 Molecular cloning, expression, and gene localization of a fourth melanocortin receptor J Biol Chem 268 15174 15179
7. Gantz I. Shimoto Y. Konda Y. Miwa H. Dickinson C.J. Yamada T. 1994 Molecular cloning, expression, and characterization of a fifth melanocortin receptor Biochem Biophys Res Commun 200 1214 1220
8. Ollmann M.M. Wilson B.D. Yang Y.K. Kerns J.A. Chen Y. Gantz I. Barsh G.S. 1997 Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein Science 278 135 138
9. Lu D. Willard D. Patel I.R. Kadwell S. Overton L. Kost T. Luther M. Chen W. Woychik R.P. Wilkison W.O. et al. 1994 Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor Nature 371 799 802
10. Eipper B.A. Mains R.E. 1980 Structure and biosynthesis of pro-ACTH/endorphin and related peptides Endocr Rev 1 1 26
11. Smith A.I. Funder J.W. 1988 Proopiomelanocortin processing in the pituitary, central nervous system and peripheral tissues Endocr Rev 9 159 179
12. Butler A.A. Kesterson R.A. Khong K. Cullen M.J. Pelleymounter M.A. Dekoning J. Baetscher M. Cone R.D. 2000 A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse Endocrinology 141 3518 3521
13. Chen A.S. Marsh D.J. Trumbauer M.E. Frazier E.G. Guan X.M. Yu H. Rosenblum C.I. Vongs A. Feng Y. Cao L. Metzger J.M. Strack A.M. Camacho R.E. Mellin T.N. Nunes C.N. et al. 2000 Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass Nat Genet 26 97 102
14. Fan W. Boston B.A. Kesterson R.A. Hruby V.J. Cone R.D. 1997 Role of melanocortinergic neurons in feeding and the agouti obesity syndrome Nature 385 165 168
15. Krude H. Biebermann H. Luck W. Horn R. Brabant G. Gruters A. 1998 Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans Nat Genet 19 155 157
16. Huszar D. Lynch C.A. Fairchild-Huntress V. Dunmore J.H. Fang Q. Berkemeier L.R. Gu W. Kesterson R.A. Boston B.A. Cone R.D. Smith F.J. Campfield L.A. Burn P. Lee F. 1997 Targeted disruption of the melanocortin-4 receptor results in obesity in mice Cell 88 131 141
17. Vaisse C. Clement K. Durand E. Hercberg S. Guy-Grand B. Froguel P. 2000 Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity J Clin Invest 106 253 262
18. Farooqi I.S. Keogh J.M. Yeo G.S. Lank E.J. Cheetham T. O'Rahilly S. 2003 Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene N Engl J Med 348 1085 1095
19. Al-Obeidi F. Castrucci A.M. Hadley M.E. Hruby V.J. 1989 Potent and prolonged acting cyclic lactam analogues of α-melanotropin: design based on molecular dynamics J Med Chem 32 2555 2561
20. 2 with bulky aromatic amino acids at position 7 show high antagonist potency and selectivity at specific melanocortin receptors J Med Chem 38 3454 3461
21. Shutter J.R. Graham M. Kinsey A.C. Scully S. Luthy R. Stark K.L. 1997 Hypothalamic expression of art, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice Genes Dev 11 593 602
22. Rossi M. Kim M.S. Morgan D.G. Small C.J. Edwards C.M. Sunter D. Abusnana S. Goldstone A.P. Russell S.H. Stanley S.A. Smith D.M. Yagaloff K. Ghatei M.A. Bloom S.R. 1998 A C-terminal fragment of agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo Endocrinology 139 4428 4431
23. Hagan M.M. Rushing P.A. Pritchard L.M. Schwartz M.W. Strack A.M. Van Der Ploeg L.H. Woods S.C. Seeley R.J. 2000 Long-term orexigenic effects of AGRP-(83-132) involve mechanisms other than melanocortin receptor blockade Am J Physiol Regul Integr Comp Physiol 279 R47 52
24. Graham M. Shutter J.R. Sarmiento U. Sarosi I. Stark K.L. 1997 Overexpression of AGRT leads to obesity in transgenic mice Nat Genet 17 273 274
25. Chai B.X. Pogozheva I.D. Lai Y.M. Li J.Y. Neubig R.R. Mosberg H.I. Gantz I. 2005 Receptor-antagonist interactions in the complexes of agouti and agouti-related protein with human melanocortin 1 and 4 receptors Biochemistry 44 3418 3431
26. Haskell-Luevano C. Monck E.K. 2001 Agouti-related protein functions as an inverse agonist at a constitutively active brain melanocortin-4 receptor Regul Pept 99 1 7
27. Nijenhuis W.A. Oosterom J. Adan R.A. 2001 Agrp(83-132) acts as an inverse agonist on the human-melanocortin-4 receptor Mol Endocrinol 15 164 171
28. Yeo G.S. Farooqi I.S. Aminian S. Halsall D.J. Stanhope R.G. O'Rahilly S. 1998 A frameshift mutation in MC4R associated with dominantly inherited human obesity Nat Genet 20 111 112
29. Vaisse C. Clement K. Guy-Grand B. Froguel P. 1998 A frameshift mutation in human MC4R is associated with a dominant form of obesity Nat Genet 20 113 114
30. Ho G. MacKenzie R.G. 1999 Functional characterization of mutations in melanocortin-4 receptor associated with human obesity J Biol Chem 274 35816 35822
31. Ohshiro Y. Sanke T. Ueda K. Shimajiri Y. Nakagawa T. Tsunoda K. Nishi M. Sasaki H. Takasu N. Nanjo K. 1999 Molecular scanning for mutations in the melanocortin-4 receptor gene in obese/diabetic Japanese Ann Hum Genet 63 483 487
32. Mergen M. Mergen H. Ozata M. Oner R. Oner C. 2001 A novel melanocortin 4 receptor (MC4R) gene mutation associated with morbid obesity J Clin Endocrinol Metab 86 3448
33. Rosmond R. Chagnon M. Bouchard C. Bjorntorp P. 2001 A missense mutation in the human melanocortin-4 receptor gene in relation to abdominal obesity and salivary cortisol Diabetologia 44 1335 1338
34. Kobayashi H. Ogawa Y. Shintani M. Ebihara K. Shimodahira M. Iwakura T. Hino M. Ishihara T. Ikekubo K. Kurahachi H. Nakao K. 2002 A novel homozygous missense mutation of melanocortin-4 receptor (MC4R) in a Japanese woman with severe obesity Diabetes 51 243 246
35. Lubrano-Berthelier C. Durand E. Dubern B. Shapiro A. Dazin P. Weill J. Ferron C. Froguel P. Vaisse C. 2003 Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations Hum Mol Genet 12 145 153
36. Lubrano-Berthelier C. Le Stunff C. Bougneres P. Vaisse C. 2004 A homozygous null mutation delineates the role of the melanocortin-4 receptor in humans J Clin Endocrinol Metab 89 2028 2032
37. Yeo G.S. Lank E.J. Farooqi I.S. Keogh J. Challis B.G. O'Rahilly S. 2003 Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms Hum Mol Genet 12 561 574
38. Marti A. Corbalan M.S. Forga L. Martinez J.A. Hinney A. Hebebrand J. 2003 A novel nonsense mutation in the melanocortin-4 receptor associated with obesity in a Spanish population Int J Obes Relat Metab Disord 27 385 388
39. Farooqi I.S. Yeo G.S. Keogh J.M. Aminian S. Jebb S.A. Butler G. Cheetham T. O'Rahilly S. 2000 Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency J Clin Invest 106 271 279
40. Nijenhuis W.A. Garner K.M. van Rozen R.J. Adan R.A. 2003 Poor cell surface expression of human melanocortin-4 receptor mutations associated with obesity J Biol Chem 278 22939 22945
41. Tao Y.X. Segaloff D.L. 2003 Functional characterization of melanocortin-4 receptor mutations associated with childhood obesity Endocrinology 144 4544 4551
42. Hinney A. Hohmann S. Geller F. Vogel C. Hess C. Wermter A.K. Brokamp B. Goldschmidt H. Siegfried W. Remschmidt H. Schafer H. Gudermann T. Hebebrand J. 2003 Melanocortin-4 receptor gene: case-control study and transmission disequilibrium test confirm that functionally relevant mutations are compatible with a major gene effect for extreme obesity J Clin Endocrinol Metab 88 4258 4267
43. Tarnow P. Schoneberg T. Krude H. Gruters A. Biebermann H. 2003 Mutationally induced disulfide bond formation within the third extracellular loop causes melanocortin 4 receptor inactivation in patients with obesity J Biol Chem 278 48666 48673
44. Ma L. Tataranni P.A. Bogardus C. Baier L.J. 2004 Melanocortin 4 receptor gene variation is associated with severe obesity in Pima Indians Diabetes 53 2696 2699
45. Valli-Jaakola K. Lipsanen-Nyman M. Oksanen L. Hollenberg A.N. Kontula K. Bjorbaek C. Schalin-Jantti C. 2004 Identification and characterization of melanocortin-4 receptor gene mutations in morbidly obese Finnish children and adults J Clin Endocrinol Metab 89 940 945
46. Donohoue P.A. Tao Y.X. Collins M. Yeo G.S. O'Rahilly S. Segaloff D.L. 2003 Deletion of codons 88-92 of the melanocortin-4 receptor gene: a novel deleterious mutation in an obese female J Clin Endocrinol Metab 88 5841 5845
47. Larsen L.H. Echwald S.M. Sorensen T.I. Andersen T. Wulff B.S. Pedersen O. 2005 Prevalence of mutations and functional analyses of melanocortin 4 receptor variants identified among 750 men with juvenile-onset obesity J Clin Endocrinol Metab 90 219 224
48. 2 at the mouse melanocortin receptors: Part 2. Modifications at the Phe position J Med Chem 45 3073 3081
49. Haskell-Luevano C. Cone R.D. Monck E.K. Wan Y.P. 2001 Structure activity studies of the melanocortin-4 receptor by in vitro mutagenesis: identification of agouti-related protein (AGRP), melanocortin agonist and synthetic peptide antagonist interaction determinants Biochemistry 40 6164 6179
50. Chen C.A. Okayama H. 1988 Calcium phosphate-medicated gene transfer: a highly efficient transfections system for stably transforming cells with plasmid DNA Biotechniques 6 632 638
51. Chen W. Shields T.S. Stork P.J. Cone R.D. 1995 A colorimetric assay for measuring activation of Gs- and Gq-coupled signaling pathways Anal Biochem 226 349 354
52. 2, a new scale for the measurement of drug antagonism Br J Pharmacol Chemother 2 189 206
53. Kopp P. van Sande J. Parma J. Duprez L. Gerber H. Joss E. Jameson J.L. Dumont J.E. Vassart G. 1995 Brief report: Congenital hyperthyroidism caused by a mutation in the thyrotropin-receptor gene N Engl J Med 332 150 154
54. Yang Y.K. Thompson D.A. Dickinson C.J. Wilken J. Barsh G.S. Kent S.B. Gantz I. 1999 Characterization of agouti-related protein binding to melanocortin receptors Mol Endocrinol 13 148 155
55. Bowen W.P. Jerman J.C. 1995 Nonlinear regression using spreadsheets Trends Pharmacol Sci 16 413 417
56. Litherland S.A. Xie X.T. Hutson A.D. Wasserfall C. Whittaker D.S. She J.-X. Hofig A. Dennis M.A. Fuller D.K. Cook R. Schatz D. Moldawer L.L. Clare-Salzler M.J. 1999 Aberrant prostaglandin synthase 2 expression defines an antigen-presenting cell defect for insulin-dependent diabetes mellitus J Clin Invest 104 515 523
57. Pogozheva I.D. Chai B.X. Lomize A.L. Fong T.M. Weinberg D.H. Nargund R.P. Mulholland M.W. Gantz I. Mosberg H.I. 2005 Interactions of human melanocortin 4 receptor with small-molecule agonists Biochemistry 44 11329 11341
58. Li J. Edwards P.C. Burghammer M. Villa C. Schertler G.F. 2004 Structure of bovine rhodopsin in a trigonal crystal form J Mol Biol 343 1409 1438
59. Fowler C.B. Pogozheva I.D. Lomize A.L. LeVine H. 3rd. Mosberg H.I. 2004 Complex of an active mu-opioid receptor with a cyclic peptide agonist modeled from experimental constraints Biochemistry 43 15796 15810
60. Riek R.P. Rigoutsos I. Novotny J. Graham R.M. 2001 Non-alpha-helical elements modulate polytopic membrane protein architecture J Mol Biol 306 349 362
61. Brooks B.R. Bruccoleri R.E. Olafson B.D. States D.J. Swaminathan S. Karplus M. 1983 CHARMM: a program for macromolecular energy, minimization, and dynamics calculation J Comput Chem 4 187 217
62. Ballesteros J.A. Weinstein H. 1995 Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein coupled receptors Methods Neurosci 25 366 428
63. Sawyer T.K. Sanfillippo P.J. Hruby V.J. Engel M.H. Heward C.B. Burnett J.B. Hadley M.E. 1980 4-Norleucine, 7-D-phenylalanine-α-melanocyte- stimulating hormone: a highly potent α-melanotropin with ultra long biological activity Proc Natl Acad Sci U S A 77 5754 5758
64. Srinivasan S. Lubrano-Berthelier C. Govaerts C. Picard F. Santiago P. Conklin B.R. Vaisse C. 2004 Constitutive activity of the melanocortin-4 receptor is maintained by its N-terminal domain and plays a role in energy homeostasis in humans J Clin Invest 114 1158 1164
65. Broberger C. Johansen J. Johansson C. Schalling M. Hokfelt T. 1998 The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice Proc Natl Acad Sci U S A 95 15043 15048
66. Haskell-Luevano C. Chen P. Li C. Chang K. Smith M.S. Cameron J.L. Cone R.D. 1999 Characterization of the neuroanatomical distribution of agouti related protein (AGRP) immunoreactivity in the rhesus monkey and the rat Endocrinology 140 1408 1415
67. Cowley M.A. Smart J.L. Rubinstein M. Cerdan M.G. Diano S. Horvath T.L. Cone R.D. Low M.J. 2001 Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus Nature 411 480 484
68. Watson S.J. Barchas J.D. Li C.H. 1977 Beta-lipotropin: localization of cells and axons in rat brain by immunocytochemistry Proc Natl Acad Sci U S A 74 5155 5158
69. Haskell-Luevano C. Chen P. Li C. Chang K. Smith M.S. Cameron J.L. Cone R.D. 1999 Characterization of the neuroanatomical distribution of agouti-related protein immunoreactivity in the rhesus monkey and the rat Endocrinology 140 1408 1415
70. Jacobowitz D.M. O'Donohue T.L. 1978 Alpha-melanocyte stimulating hormone: immunohistochemical identification and mapping in neurons of rat brain Proc Natl Acad Sci U S A 75 6300 6304
71. Khachaturian H. Lewis M.E. Haber S.N. Akil H. Watson S.J. 1984 Proopiomelanocortin peptide immunocytochemistry in rhesus monkey brain Brain Res Bull 13 785 800
72. Finley J.C. Lindstrom P. Petrusz P. 1981 Immunocytochemical localization of beta-endorphin-containing neurons in the rat brain Neuroendocrinology 33 28 42
73. Thornton J.E. Cheung C.C. Clifton D.K. Steiner R.A. 1997 Regulation of hypothalamic proopiomelanocortin mRNA by leptin in ob/ob mice Endocrinology 138 5063 5066
74. Mizuno T.M. Kleopoulos S.P. Bergen H.T. Roberts J.L. Priest C.A. Mobbs C.V. 1998 Hypothalamic pro-opiomelanocortin mRNA is reduced by fasting and corrected in ob/ob and db/db mice, but is stimulated by leptin Diabetes 47 294 297
75. Pei G. Samama P. Lohse M. Wang M. Codina J. Lefkowitz R.J. 1994 A constitutively active mutant beta 2-adrenergic receptor is constitutively desensitized and phosphorylated Proc Natl Acad Sci U S A 91 2699 2702
76. Jin S. Cornwall M.C. Oprian D.D. 2003 Opsin activation as a cause of congenital night blindness Nat Neurosci 6 731 735
77. Kenakin T. 2004 Efficacy as a vector: the relative prevalence and paucity of inverse agonism Mol Pharmacol 65 2 11
78. Costa T. Herz A. 1989 Antagonists with negative intrinsic activity at delta opioid receptors coupled to GTP-binding proteins Proc Natl Acad Sci U S A 86 7321 7325
79. Okada T. Ernst O.P. Palczewski K. Hofmann K.P. 2001 Activation of rhodopsin: new insights from structural and biochemical studies Trends Biochem Sci 26 318 324
80. Meng E.C. Bourne H.R. 2001 Receptor activation: what does the rhodopsin structure tell us Trends Pharmacol Sci 22 587 593
81. Gether U. Asmar F. Meinild A.K. Rasmussen S.G. 2002 Structural basis for activation of G-protein-coupled receptors Pharmacol Toxicol 91 304 312
82. Patel A.B. Crocker E. Reeves P.J. Getmanova E.V. Eilers M. Khorana H.G. Smith S.O. 2005 Changes in interhelical hydrogen bonding upon rhodopsin activation J Mol Biol 347 803 812
83. Fritze O. Filipek S. Kuksa V. Palczewski K. Hofmann K.P. Ernst O.P. 2003 Role of the conserved NPXXY(X)5,6F motif in the rhodopsin ground state and during activation Proc Natl Acad Sci U S A 100 2290 2295
84. Li B. Nowak N.M. Kim S.K. Jacobson K.A. Bagheri A. Schmidt C. Wess J. 2005 Random mutagenesis of the m3 muscarinic acetylcholine receptor expressed in yeast: identification of second-site mutations that restore function to a coupling-deficient mutant m3 receptor J Biol Chem 280 5664 5675
85. Zhang M. Mizrachi D. Fanelli F. Segaloff D.L. 2005 The formation of a salt bridge between helices 3 and 6 is responsible for the constitutive activity and lack of hormone responsiveness of the naturally occurring L457R mutation of the human lutropin receptor J Biol Chem 280 26169 26176
86. Alves I.D. Cowell S.M. Salamon Z. Devanathan S. Tollin G. Hruby V.J. 2004 Different structural states of the proteolipid membrane are produced by ligand binding to the human delta-opioid receptor as shown by plasmon-waveguide resonance spectroscopy Mol Pharmacol 65 1248 1257
87. Devanathan S. Yao Z. Salamon Z. Kobilka B. Tollin G. 2004 Plasmon-waveguide resonance studies of ligand binding to the human beta 2-adrenergic receptor Biochemistry 43 3280 3288
88. Kobilka B.K. 2002 Agonist-induced conformational changes in the beta2 adrenergic receptor J Pept Res 60 317 321
89. Alves I.D. Ciano K.A. Boguslavski V. Varga E. Salamon Z. Yamamura H.I. Hruby V.J. Tollin G. 2004 Selectivity, cooperativity, and reciprocity in the interactions between the delta-opioid receptor, its ligands, and g-proteins J Biol Chem 279 44673 44682
90. Han M. Smith S.O. Sakmar T.P. 1998 Constitutive activation of opsin by mutation of methionine 257 on transmembrane helix 6 Biochemistry 37 8253 8261