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Structures of the agouti signaling protein.

McNulty JC, Jackson PJ, Thompson DA, Chai B, Gantz I, Barsh GS, Dawson PE, Millhauser GL
J Mol Biol 346 1059-70 (2005)
Related entries: 1mr0, 1y7j

Cited: 59 times
EuropePMC logo PMID: 15701517

Abstract

Expression of the agouti signaling protein (ASIP) during hair growth produces the red/yellow pigment pheomelanin. ASIP, and its neuropeptide homolog the agouti-related protein (AgRP) involved in energy balance, are novel, paracrine signaling molecules that act as inverse agonists at distinct subsets of melanocortin receptors. Ubiquitous ASIP expression in mice gives rise to a pleiotropic phenotype characterized by a uniform yellow coat color, obesity, overgrowth, and metabolic derangements similar to type II diabetes in humans. Here we report the synthesis and NMR structure of ASIP's active, cysteine-rich, C-terminal domain. ASIP adopts the inhibitor cystine knot fold and, along with AgRP, are the only known mammalian proteins in this structure class. Moreover, ASIP populates two distinct conformers resulting from a cis peptide bond at Pro102-Pro103 and a coexistence of cis/trans isomers of Ala104-Pro105. Pharmacologic studies of Pro-->Ala mutants demonstrate that the minor conformation with two cis peptide bonds is responsible for activity at all MCRs. The loop containing the heterogeneous Ala-Pro peptide bond is conserved in mammals, and suggests that ASIP is either trapped by evolution in this unusual configuration or possesses function outside of strict MCR antagonism.

Articles - 1y7k mentioned but not cited (2)

  1. Molecular and functional analysis of human β-defensin 3 action at melanocortin receptors. Nix MA, Kaelin CB, Ta T, Weis A, Morton GJ, Barsh GS, Millhauser GL. Chem Biol 20 784-795 (2013)
  2. Structure-Activity Relationship Studies on a Macrocyclic Agouti-Related Protein (AGRP) Scaffold Reveal Agouti Signaling Protein (ASP) Residue Substitutions Maintain Melanocortin-4 Receptor Antagonist Potency and Result in Inverse Agonist Pharmacology at the Melanocortin-5 Receptor. Ericson MD, Freeman KT, Schnell SM, Fleming KA, Haskell-Luevano C. J Med Chem 60 8103-8114 (2017)


Reviews citing this publication (9)

  1. Melanocortin 1 Receptor: Structure, Function, and Regulation. Wolf Horrell EM, Boulanger MC, D'Orazio JA. Front Genet 7 95 (2016)
  2. Molecular genetics of human obesity: A comprehensive review. Singh RK, Kumar P, Mahalingam K. C R Biol 340 87-108 (2017)
  3. Melanocortin MC₁ receptor in human genetics and model systems. Beaumont KA, Wong SS, Ainger SA, Liu YY, Patel MP, Millhauser GL, Smith JJ, Alewood PF, Leonard JH, Sturm RA. Eur J Pharmacol 660 103-110 (2011)
  4. New ligands for melanocortin receptors. Kaelin CB, Candille SI, Yu B, Jackson P, Thompson DA, Nix MA, Binkley J, Millhauser GL, Barsh GS. Int J Obes (Lond) 32 Suppl 7 S19-27 (2008)
  5. Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016. Ericson MD, Lensing CJ, Fleming KA, Schlasner KN, Doering SR, Haskell-Luevano C. Biochim Biophys Acta Mol Basis Dis 1863 2414-2435 (2017)
  6. The Melanocortin Receptor System: A Target for Multiple Degenerative Diseases. Cai M, Hruby VJ. Curr Protein Pept Sci 17 488-496 (2016)
  7. Chemical synthesis, backbone cyclization and oxidative folding of cystine-knot peptides: promising scaffolds for applications in drug design. Reinwarth M, Nasu D, Kolmar H, Avrutina O. Molecules 17 12533-12552 (2012)
  8. The melanocortin pathway and energy homeostasis: From discovery to obesity therapy. Yeo GSH, Chao DHM, Siegert AM, Koerperich ZM, Ericson MD, Simonds SE, Larson CM, Luquet S, Clarke I, Sharma S, Clément K, Cowley MA, Haskell-Luevano C, Van Der Ploeg L, Adan RAH. Mol Metab 48 101206 (2021)
  9. From Bioinactive ACTH to ACTH Antagonist: The Clinical Perspective. Ghaddhab C, Vuissoz JM, Deladoëy J. Front Endocrinol (Lausanne) 8 17 (2017)

Articles citing this publication (48)

  1. A -defensin mutation causes black coat color in domestic dogs. Candille SI, Kaelin CB, Cattanach BM, Yu B, Thompson DA, Nix MA, Kerns JA, Schmutz SM, Millhauser GL, Barsh GS. Science 318 1418-1423 (2007)
  2. The serine protease Corin is a novel modifier of the Agouti pathway. Enshell-Seijffers D, Lindon C, Morgan BA. Development 135 217-225 (2008)
  3. Defining MC1R regulation in human melanocytes by its agonist α-melanocortin and antagonists agouti signaling protein and β-defensin 3. Swope VB, Jameson JA, McFarland KL, Supp DM, Miller WE, McGraw DW, Patel MA, Nix MA, Millhauser GL, Babcock GF, Abdel-Malek ZA. J Invest Dermatol 132 2255-2262 (2012)
  4. Melanoma prevention strategy based on using tetrapeptide alpha-MSH analogs that protect human melanocytes from UV-induced DNA damage and cytotoxicity. Abdel-Malek ZA, Kadekaro AL, Kavanagh RJ, Todorovic A, Koikov LN, McNulty JC, Jackson PJ, Millhauser GL, Schwemberger S, Babcock G, Haskell-Luevano C, Knittel JJ. FASEB J 20 1561-1563 (2006)
  5. More than 1,001 problems with protein domain databases: transmembrane regions, signal peptides and the issue of sequence homology. Wong WC, Maurer-Stroh S, Eisenhaber F. PLoS Comput Biol 6 e1000867 (2010)
  6. Voluntary exercise prevents the obese and diabetic metabolic syndrome of the melanocortin-4 receptor knockout mouse. Haskell-Luevano C, Schaub JW, Andreasen A, Haskell KR, Moore MC, Koerper LM, Rouzaud F, Baker HV, Millard WJ, Walter G, Litherland SA, Xiang Z. FASEB J 23 642-655 (2009)
  7. Agouti protein, mahogunin, and attractin in pheomelanogenesis and melanoblast-like alteration of melanocytes: a cAMP-independent pathway. Hida T, Wakamatsu K, Sviderskaya EV, Donkin AJ, Montoliu L, Lynn Lamoreux M, Yu B, Millhauser GL, Ito S, Barsh GS, Jimbow K, Bennett DC. Pigment Cell Melanoma Res 22 623-634 (2009)
  8. Grafting of thrombopoietin-mimetic peptides into cystine knot miniproteins yields high-affinity thrombopoietin antagonists and agonists. Krause S, Schmoldt HU, Wentzel A, Ballmaier M, Friedrich K, Kolmar H. FEBS J 274 86-95 (2007)
  9. Knottin cyclization: impact on structure and dynamics. Heitz A, Avrutina O, Le-Nguyen D, Diederichsen U, Hernandez JF, Gracy J, Kolmar H, Chiche L. BMC Struct Biol 8 54 (2008)
  10. Structural and molecular evolutionary analysis of Agouti and Agouti-related proteins. Jackson PJ, Douglas NR, Chai B, Binkley J, Sidow A, Barsh GS, Millhauser GL. Chem Biol 13 1297-1305 (2006)
  11. Effects of i and i+3 residue identity on cis-trans isomerism of the aromatic(i+1)-prolyl(i+2) amide bond: implications for type VI beta-turn formation. Meng HY, Thomas KM, Lee AE, Zondlo NJ. Biopolymers 84 192-204 (2006)
  12. Transcriptome sequencing reveals differences between primary and secondary hair follicle-derived dermal papilla cells of the Cashmere goat (Capra hircus). Zhu B, Xu T, Yuan J, Guo X, Liu D. PLoS One 8 e76282 (2013)
  13. Characterization and tissue distribution of multiple agouti-family genes in pufferfish, Takifugu rubripes. Kurokawa T, Murashita K, Uji S. Peptides 27 3165-3175 (2006)
  14. Coat colours in the Massese sheep breed are associated with mutations in the agouti signalling protein (ASIP) and melanocortin 1 receptor (MC1R) genes. Fontanesi L, Dall'Olio S, Beretti F, Portolano B, Russo V. Animal 5 8-17 (2011)
  15. Development of a high throughput screen for allosteric modulators of melanocortin-4 receptor signaling using a real time cAMP assay. Pantel J, Williams SY, Mi D, Sebag J, Corbin JD, Weaver CD, Cone RD. Eur J Pharmacol 660 139-147 (2011)
  16. Engineering agatoxin, a cystine-knot peptide from spider venom, as a molecular probe for in vivo tumor imaging. Moore SJ, Leung CL, Norton HK, Cochran JR. PLoS One 8 e60498 (2013)
  17. The alpaca agouti gene: genomic locus, transcripts and causative mutations of eumelanic and pheomelanic coat color. Chandramohan B, Renieri C, La Manna V, La Terza A. Gene 521 303-310 (2013)
  18. Loop-swapped chimeras of the agouti-related protein and the agouti signaling protein identify contacts required for melanocortin 1 receptor selectivity and antagonism. Patel MP, Cribb Fabersunne CS, Yang YK, Kaelin CB, Barsh GS, Millhauser GL. J Mol Biol 404 45-55 (2010)
  19. Melanocortin-1 receptor-mediated signalling pathways activated by NDP-MSH and HBD3 ligands. Beaumont KA, Smit DJ, Liu YY, Chai E, Patel MP, Millhauser GL, Smith JJ, Alewood PF, Sturm RA. Pigment Cell Melanoma Res 25 370-374 (2012)
  20. Targeting protein-trafficking pathways alters melanoma treatment sensitivity. Huang ZM, Chinen M, Chang PJ, Xie T, Zhong L, Demetriou S, Patel MP, Scherzer R, Sviderskaya EV, Bennett DC, Millhauser GL, Oh DH, Cleaver JE, Wei ML. Proc Natl Acad Sci U S A 109 553-558 (2012)
  21. Genome Wide Association Study Identifies New Loci Associated with Undesired Coat Color Phenotypes in Saanen Goats. Martin PM, Palhière I, Ricard A, Tosser-Klopp G, Rupp R. PLoS One 11 e0152426 (2016)
  22. Investigation of the role of the agouti signaling protein gene (ASIP) in coat color evolution in primates. Mundy NI, Kelly J. Mamm Genome 17 1205-1213 (2006)
  23. Resveratrol, purified from the stem of Vitis coignetiae Pulliat, inhibits food intake in C57BL/6J Mice. Kim SJ, Lee YH, Han MD, Mar W, Kim WK, Nam KW. Arch Pharm Res 33 775-780 (2010)
  24. Discovery of Novel Potent and Selective Agonists at the Melanocortin-3 Receptor. Carotenuto A, Merlino F, Cai M, Brancaccio D, Yousif AM, Novellino E, Hruby VJ, Grieco P. J Med Chem 58 9773-9778 (2015)
  25. Identification of single nucleotide polymorphisms in the agouti signaling protein (ASIP) gene in some goat breeds in tropical and temperate climates. Adefenwa MA, Peters SO, Agaviezor BO, Wheto M, Adekoya KO, Okpeku M, Oboh B, Williams GO, Adebambo OA, Singh M, Thomas B, De Donato M, Imumorin IG. Mol Biol Rep 40 4447-4457 (2013)
  26. An unusual conformation of γ-melanocyte-stimulating hormone analogues leads to a selective human melanocortin 1 receptor antagonist for targeting melanoma cells. Cai M, Stankova M, Muthu D, Mayorov A, Yang Z, Trivedi D, Cabello C, Hruby VJ. Biochemistry 52 752-764 (2013)
  27. How the leopard hides its spots: ASIP mutations and melanism in wild cats. Schneider A, David VA, Johnson WE, O'Brien SJ, Barsh GS, Menotti-Raymond M, Eizirik E. PLoS One 7 e50386 (2012)
  28. Countershading in zebrafish results from an Asip1 controlled dorsoventral gradient of pigment cell differentiation. Cal L, Suarez-Bregua P, Comesaña P, Owen J, Braasch I, Kelsh R, Cerdá-Reverter JM, Rotllant J. Sci Rep 9 3449 (2019)
  29. Structure-Activity Relationship Studies of a Macrocyclic AGRP-Mimetic Scaffold c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-DPro] Yield Potent and Selective Melanocortin-4 Receptor Antagonists and Melanocortin-5 Receptor Inverse Agonists That Increase Food Intake in Mice. Fleming KA, Ericson MD, Freeman KT, Adank DN, Lunzer MM, Wilber SL, Haskell-Luevano C. ACS Chem Neurosci 9 1141-1151 (2018)
  30. Synthesis, biophysical, and pharmacological evaluation of the melanocortin agonist AST3-88: modifications of peptide backbone at Trp 7 position lead to a potent, selective, and stable ligand of the melanocortin 4 receptor (MC4R). Singh A, Dirain ML, Wilczynski A, Chen C, Gosnell BA, Levine AS, Edison AS, Haskell-Luevano C. ACS Chem Neurosci 5 1020-1031 (2014)
  31. Whole genome analysis of water buffalo and global cattle breeds highlights convergent signatures of domestication. Dutta P, Talenti A, Young R, Jayaraman S, Callaby R, Jadhav SK, Dhanikachalam V, Manikandan M, Biswa BB, Low WY, Williams JL, Cook E, Toye P, Wall E, Djikeng A, Marshall K, Archibald AL, Gokhale S, Kumar S, Hume DA, Prendergast JGD. Nat Commun 11 4739 (2020)
  32. A missense mutation in the agouti signaling protein gene (ASIP) is associated with the no light points coat phenotype in donkeys. Abitbol M, Legrand R, Tiret L. Genet Sel Evol 47 28 (2015)
  33. Substitution of arginine with proline and proline derivatives in melanocyte-stimulating hormones leads to selectivity for human melanocortin 4 receptor. Qu H, Cai M, Mayorov AV, Grieco P, Zingsheim M, Trivedi D, Hruby VJ. J Med Chem 52 3627-3635 (2009)
  34. Chemical disulfide mapping identifies an inhibitor cystine knot in the agouti signaling protein. Yu B, Millhauser GL. FEBS Lett 581 5561-5565 (2007)
  35. Molecular cloning and in silico characterization of knottin peptide, U2-SCRTX-Lit2, from brown spider (Loxosceles intermedia) venom glands. Meissner GO, de Resende Lara PT, Scott LP, Braz AS, Chaves-Moreira D, Matsubara FH, Soares EM, Trevisan-Silva D, Gremski LH, Veiga SS, Chaim OM. J Mol Model 22 196 (2016)
  36. Solid-phase peptide head-to-side chain cyclodimerization: discovery of C(2)-symmetric cyclic lactam hybrid α-melanocyte-stimulating hormone (MSH)/agouti-signaling protein (ASIP) analogues with potent activities at the human melanocortin receptors. Mayorov AV, Cai M, Palmer ES, Liu Z, Cain JP, Vagner J, Trivedi D, Hruby VJ. Peptides 31 1894-1905 (2010)
  37. Agouti signalling protein is an inverse agonist to the wildtype and agonist to the melanic variant of the melanocortin-1 receptor in the grey squirrel (Sciurus carolinensis). McRobie HR, King LM, Fanutti C, Symmons MF, Coussons PJ. FEBS Lett 588 2335-2343 (2014)
  38. Agouti-related protein segments outside of the receptor binding core are required for enhanced short- and long-term feeding stimulation. Madonna ME, Schurdak J, Yang YK, Benoit S, Millhauser GL. ACS Chem Biol 7 395-402 (2012)
  39. Electrostatic Similarity Analysis of Human β-Defensin Binding in the Melanocortin System. Nix MA, Kaelin CB, Palomino R, Miller JL, Barsh GS, Millhauser GL. Biophys J 109 1946-1958 (2015)
  40. Genetics of Sex-linked yellow in the Syrian hamster. Alizadeh A, Hong LZ, Kaelin CB, Raudsepp T, Manuel H, Barsh GS. Genetics 181 1427-1436 (2009)
  41. Recurrent evolution of melanism in South American felids. Schneider A, Henegar C, Day K, Absher D, Napolitano C, Silveira L, David VA, O'Brien SJ, Menotti-Raymond M, Barsh GS, Eizirik E. PLoS Genet 11 e1004892 (2015)
  42. Multiple origins of melanism in two species of North American tree squirrel (Sciurus). McRobie HR, Moncrief ND, Mundy NI. BMC Evol Biol 19 140 (2019)
  43. Arg-Phe-Phe d-Amino Acid Stereochemistry Scan in the Macrocyclic Agouti-Related Protein Antagonist Scaffold c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro] Results in Unanticipated Melanocortin-1 Receptor Agonist Profiles. Ericson MD, Koerperich ZM, Freeman KT, Fleming KA, Haskell-Luevano C. ACS Chem Neurosci 9 3015-3023 (2018)
  44. Potential Causative Mutation for Melanism in Rats Identified in the Agouti Signaling Protein Gene (Asip) of the Rattus rattus Species Complex on Okinawa Island, Japan. Sasamori S, Wiewel AS, Thomson VA, Kobayashi M, Nakata K, Suzuki H. Zoolog Sci 34 513-522 (2017)
  45. A workflow for in silico design of hIL-10 and ebvIL-10 inhibitors using well-known miniprotein scaffolds. Dueñas S, Aguila SA, Pimienta G. J Mol Model 23 118 (2017)
  46. Discovery of a Pan-Melanocortin Receptor Antagonist [Ac-DPhe(pI)-Arg-Nal(2')-Orn-NH2] at the MC1R, MC3R, MC4R, and MC5R that Mediates an Increased Feeding Response in Mice and a 40-Fold Selective MC1R Antagonist [Ac-DPhe(pI)-DArg-Nal(2')-Arg-NH2]. Ericson MD, Tran LT, Mathre SS, Freeman KT, Holdaway K, John K, Lunzer MM, Bouchard JL, Haskell-Luevano C. J Med Chem 66 8103-8117 (2023)
  47. New Insectotoxin from Tibellus Oblongus Spider Venom Presents Novel Adaptation of ICK Fold. Korolkova Y, Maleeva E, Mikov A, Lobas A, Solovyeva E, Gorshkov M, Andreev Y, Peigneur S, Tytgat J, Kornilov F, Lushpa V, Mineev K, Kozlov S. Toxins (Basel) 13 (2021)
  48. Serum levels of hormones regulating appetite in patients with cystic fibrosis - a single-center, cross-sectional study. Galiniak S, Podgórski R, Rachel M, Mazur A. Front Endocrinol (Lausanne) 13 992667 (2022)


Related citations provided by authors (2)

  1. High-resolution NMR structure of the chemically-synthesized melanocortin receptor binding domain AGRP(87-132) of the agouti-related protein.. McNulty JC, Thompson DA, Bolin KA, Wilken J, Barsh GS, Millhauser GL Biochemistry 40 15520-7 (2001)
  2. Design, pharmacology, and NMR structure of a minimized cystine knot with agouti-related protein activity.. Jackson PJ, McNulty JC, Yang YK, Thompson DA, Chai B, Gantz I, Barsh GS, Millhauser GL Biochemistry 41 7565-72 (2002)

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