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NMR structure of a minimized human agouti related protein prepared by total chemical synthesis.

Bolin KA, Anderson DJ, Trulson JA, Thompson DA, Wilken J, Kent SB, Gantz I, Millhauser GL
FEBS Lett 451 125-31 (1999)
Cited: 56 times
EuropePMC logo PMID: 10371151

Abstract

The structure of the chemically synthesized C-terminal region of the human agouti related protein (AGRP) was determined by 2D 1H NMR. Referred to as minimized agouti related protein, MARP is a 46 residue polypeptide containing 10 Cys residues involved in five disulfide bonds that retains the biological activity of full length AGRP. AGRP is a mammalian signaling molecule, involved in weight homeostasis, that causes adult onset obesity when overexpressed in mice. AGRP was originally identified by homology to the agouti protein, another potent signaling molecule involved in obesity disorders in mice. While AGRP's exact mechanism of action is unknown, it has been identified as a competitive antagonist of melanocortin receptors 3 and 4 (MC3r, MC4r), and MC4r in particular is implicated in the hypothalamic control of feeding behavior. Full length agouti and AGRP are only 25% homologous, however, their active C-terminal regions are approximately 40% homologous, with nine out of the 10 Cys residues spatially conserved. Until now, 3D structures have not been available for either agouti, AGRP or their C-terminal regions. The NMR structure of MARP reported here can be characterized as three major loops, with four of the five disulfide bridges at the base of the structure. Though its fold is well defined, no canonical secondary structure is identified. While previously reported structural models of the C-terminal region of AGRP were attempted based on Cys homology between AGRP and certain toxin proteins, we find that Cys spacing is not sufficient to correctly determine the 3D fold of the molecule.

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  11. Current trends in the structure-activity relationship studies of the endogenous agouti-related protein (AGRP) melanocortin receptor antagonist. Wilczynski AM, Joseph CG, Haskell-Luevano C. Med Res Rev 25 545-556 (2005)
  12. A Review of Single-Nucleotide Polymorphisms in Orexigenic Neuropeptides Targeting G Protein-Coupled Receptors. Ericson MD, Haskell-Luevano C. ACS Chem Neurosci 9 1235-1246 (2018)

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  2. Characterization of the dog Agouti gene and a nonagoutimutation in German Shepherd Dogs. Kerns JA, Newton J, Berryere TG, Rubin EM, Cheng JF, Schmutz SM, Barsh GS. Mamm Genome 15 798-808 (2004)
  3. 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 1059-1070 (2005)
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  5. Pineal-specific agouti protein regulates teleost background adaptation. Zhang C, Song Y, Thompson DA, Madonna MA, Millhauser GL, Toro S, Varga Z, Westerfield M, Gamse J, Chen W, Cone RD. Proc Natl Acad Sci U S A 107 20164-20171 (2010)
  6. Characterization and tissue distribution of multiple agouti-family genes in pufferfish, Takifugu rubripes. Kurokawa T, Murashita K, Uji S. Peptides 27 3165-3175 (2006)
  7. Molecular and phenotypic analysis of 25 recessive, homozygous-viable alleles at the mouse agouti locus. Miltenberger RJ, Wakamatsu K, Ito S, Woychik RP, Russell LB, Michaud EJ. Genetics 160 659-674 (2002)
  8. Agouti related protein in the rat adrenal cortex: implications for novel autocrine mechanisms modulating the actions of pro-opiomelanocortin peptides. Bicknell AB, Lomthaisong K, Gladwell RT, Lowry PJ. J Neuroendocrinol 12 977-982 (2000)
  9. Discovery of a β-Hairpin Octapeptide, c[Pro-Arg-Phe-Phe-Dap-Ala-Phe-DPro], Mimetic of Agouti-Related Protein(87-132) [AGRP(87-132)] with Equipotent Mouse Melanocortin-4 Receptor (mMC4R) Antagonist Pharmacology. Ericson MD, Wilczynski A, Sorensen NB, Xiang Z, Haskell-Luevano C. J Med Chem 58 4638-4647 (2015)
  10. 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)
  11. Agouti-related proteins (AGRPs) and agouti-signaling peptide (ASIP) in fish and chicken. Klovins J, Schiöth HB. Ann N Y Acad Sci 1040 363-367 (2005)
  12. Transient ectopic overexpression of agouti-signalling protein 1 (asip1) induces pigment anomalies in flatfish. Guillot R, Ceinos RM, Cal R, Rotllant J, Cerdá-Reverter JM. PLoS One 7 e48526 (2012)
  13. 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)
  14. Molecular determination of agouti-related protein binding to human melanocortin-4 receptor. Yang Y, Chen M, Lai Y, Gantz I, Yagmurlu A, Georgeson KE, Harmon CM. Mol Pharmacol 64 94-103 (2003)
  15. The agouti-related protein decapeptide (Yc[CRFFNAFC]Y) possesses agonist activity at the murine melanocortin-1 receptor. Haskell-Luevano C, Monck EK, Wan YP, Schentrup AM. Peptides 21 683-689 (2000)
  16. Molecular basis of melanocortin-4 receptor for AGRP inverse agonism. Chen M, Celik A, Georgeson KE, Harmon CM, Yang Y. Regul Pept 136 40-49 (2006)
  17. Elongation studies of the human agouti-related protein (AGRP) core decapeptide (Yc[CRFFNAFC]Y) results in antagonism at the mouse melanocortin-3 receptor. Joseph CG, Bauzo RM, Xiang Z, Shaw AM, Millard WJ, Haskell-Luevano C. Peptides 24 263-270 (2003)
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  19. Chimeras of the agouti-related protein: insights into agonist and antagonist selectivity of melanocortin receptors. Jackson PJ, Yu B, Hunrichs B, Thompson DA, Chai B, Gantz I, Millhauser GL. Peptides 26 1978-1987 (2005)
  20. Chimeric NDP-MSH and MTII melanocortin peptides with agouti-related protein (AGRP) Arg-Phe-Phe amino acids possess agonist melanocortin receptor activity. Joseph CG, Wilczynski A, Holder JR, Xiang Z, Bauzo RM, Scott JW, Haskell-Luevano C. Peptides 24 1899-1908 (2003)
  21. Functional properties of an agouti signaling protein variant and characteristics of its cognate radioligand. Yang YK, Dickinson C, Lai YM, Li JY, Gantz I. Am J Physiol Regul Integr Comp Physiol 281 R1877-86 (2001)
  22. Peptoid mimics of agouti related protein. Thompson DA, Chai BX, Rood HL, Siani MA, Douglas NR, Gantz I, Millhauser GL. Bioorg Med Chem Lett 13 1409-1413 (2003)
  23. 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)
  24. Synergistic Multiresidue Substitutions of a Macrocyclic c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-dPro] Agouti-Related Protein (AGRP) Scaffold Yield Potent and >600-Fold MC4R versus MC3R Selective Melanocortin Receptor Antagonists. Fleming KA, Freeman KT, Ericson MD, Haskell-Luevano C. J Med Chem 61 7729-7740 (2018)
  25. A Macrocyclic Agouti-Related Protein/[Nle4,DPhe7]α-Melanocyte Stimulating Hormone Chimeric Scaffold Produces Subnanomolar Melanocortin Receptor Ligands. Ericson MD, Freeman KT, Schnell SM, Haskell-Luevano C. J Med Chem 60 805-813 (2017)
  26. 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)
  27. Co-expression of human agouti-related protein enhances expression and stability of human melanocortin-4 receptor. Yun JH, Kim K, Jung Y, Park JH, Cho HS, Lee W. Biochem Biophys Res Commun 456 116-121 (2015)
  28. Discovery of Molecular Interactions of the Human Melanocortin-4 Receptor (hMC4R) Asp189 (D189) Amino Acid with the Endogenous G-Protein-Coupled Receptor (GPCR) Antagonist Agouti-Related Protein (AGRP) Provides Insights to AGRP's Inverse Agonist Pharmacology at the hMC4R. Ericson MD, Haslach EM, Schnell SM, Freeman KT, Xiang ZM, Portillo FP, Speth R, Litherland SA, Haskell-Luevano C. ACS Chem Neurosci 12 542-556 (2021)
  29. In vitro and in vivo effect of parathyroid hormone analogue (1-14) containing -amino-iso-butyric acid residue (Aib)1,3. Rhee Y, Lee W, Lee EJ, Ma S, Park SY, Lim SK. Yonsei Med J 47 214-222 (2006)
  30. Peptoid NPhe4 in AGRP-Based c[Pro1-Arg2-Phe3-Phe4-Xxx5-Ala6-Phe7-DPro8] Scaffolds Maintain Mouse MC4R Antagonist Potency. Ericson MD, Freeman KT, Haskell-Luevano C. ACS Med Chem Lett 11 1942-1948 (2020)
  31. Redox regulation of KV7 channels through EF3 hand of calmodulin. Nuñez E, Jones F, Muguruza-Montero A, Urrutia J, Aguado A, Malo C, Bernardo-Seisdedos G, Domene C, Millet O, Gamper N, Villarroel A. Elife 12 e81961 (2023)


Related citations provided by authors (2)

  1. Characterization of Agouti-related protein binding to melanocortin receptors.. Yang YK, Thompson DA, Dickinson CJ, Wilken J, Barsh GS, Kent SB, Gantz I Mol Endocrinol 13 148-55 (1999)
  2. Determination of disulfide structure in agouti-related protein (AGRP) by stepwise reduction and alkylation.. Bures EJ, Hui JO, Young Y, Chow DT, Katta V, Rohde MF, Zeni L, Rosenfeld RD, Stark KL, Haniu M Biochemistry 37 12172-7 (1998)

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