Molecular Interaction of Agouti Protein and Agouti-Related Protein with Human Melanocortin Receptors

Tota, Michael R.; Smith, Todd; Mao, Catherine D.; MacNeil, Tanya; Mosley, Ralph T.; Ploeg, Lex H.T. Van der; Fong, Tung M.

doi:10.1021/bi9815602

Cited by 101 publications

(171 citation statements)

References 22 publications

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“…The central loop AGRP 106 -119 containing Arg-Phe-Phe may be critical for AGRP function, whereas the N-and C-terminal loops of AGRP 87-132 may confer receptor subtype specificity (Bolin et al, 1999). The Arg-Phe-Phe in AGRP may resemble the properties of PheArg-Trp in ␣-MSH, His-(D-Phe)-Arg-Trp in MT-II (an analogue of ␣-MSH), or His-(D-Nal)-Arg-Trp in SHU9119 (an antagonist of MC4R) (Hruby et al, 1995;Tota et al, 1999). Therefore, AGRP 110 -117 is particularly interesting because it is a relatively small, simple peptide consisting of only seven amino acids in the C-terminal of AGRP, AGRP 110 -117.…”

Section: Discussionmentioning

confidence: 99%

Molecular Determination of Agouti-Related Protein Binding to Human Melanocortin-4 Receptor

Yang

Chen²,

Lai³

et al. 2003

Mol Pharmacol

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Agouti-related protein (AGRP) is an endogenous antagonist of the melanocortin-4 receptor (MC4R) that functions in the hypothalamic control of feeding behavior. Our previous studies have suggested that in addition to exoloops 2 and 3, several transmembrane domains of MC4R may be important for AGRP binding. However, the detailed molecular basis of MC4R domains in AGRP binding is presently unclear. The present studies were designed to determine the specific contribution of MC4R exoloops and transmembrane domains to AGRP binding by using chimeric receptor constructs of the human melanocortin-1 receptor (hMC1R), a receptor that is not inhibited by AGRP, and the human MC4R (hMC4R), a receptor that is potently inhibited by AGRP. Our results indicate that substitutions of the second and third extracellular loops of the MC4R with homologous domains of the MC1R dramatically decreased AGRP 87-132 binding affinity, but did not affect AGRP 110 -117 binding affinity. In contrast, cassette substitutions of the third or fourth transmembrane domain of the MC4R with the homologous domain of the MC1R resulted in a substantial decrease of AGRP 87-132 binding affinity and loss of AGRP 110 -117 binding affinity. These data suggest that the AGRP fragment 110 -117 has no binding sites at exoloops of hMC4R and that transmembrane domains of MC4R may play an important role in AGRP 110 -117 binding and function, whereas the exoloops do not. The second and third extracellular loops of MC4R are important for AGRP 87-132 N-terminal binding, whereas the third and fourth transmembrane domains of hMC4R are crucial for AGRP 110 -117 binding.

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Section: Discussionmentioning

confidence: 99%

Molecular Determination of Agouti-Related Protein Binding to Human Melanocortin-4 Receptor

Yang

Chen²,

Lai³

et al. 2003

Mol Pharmacol

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“…Previous modeling efforts have suggested that AGRP(87-132) shares homology with ω-agatoxin IVB, which adopts the ICK fold (36). First identified for nerve growth factors, the cystine knot is now recognized as a general scaffold for a wide range of proteins (38,39).…”

Section: Discussionmentioning

confidence: 99%

“…In AGRP(87-132), the replacement of triplet residue Arg111 with Ala eliminates the protein's ability to inhibit NDP-MSH (a potent analogue of R-MSH) stimulated cAMP production in MC4R transfected cells (20). Tota et al (36) reasoned that the RFF triplet forms a primary contact point for the ligand-receptor interaction. Their hypothesis was tested by screening short cyclic peptides (corresponding to the active loop defined here) derived from the RFFcontaining region of agouti and AGRP for MC3R and MC4R antagonism.…”

Section: Discussionmentioning

confidence: 99%

High-Resolution NMR Structure of the Chemically-Synthesized Melanocortin Receptor Binding Domain AGRP(87−132) of the Agouti-Related Protein^,

et al. 2001

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The agouti-related protein (AGRP) is an endogenous antagonist of the melanocortin receptors MC3R and MC4R found in the hypothalamus and exhibits potent orexigenic (appetite-stimulating) activity. The cysteine-rich C-terminal domain of this protein, corresponding to AGRP(87-132), contains five disulfide bonds and exhibits receptor binding affinity and antagonism equivalent to that of the full-length protein. The three-dimensional structure of this domain has been determined by 1 H NMR at 800 MHz. The first 34 residues of AGRP(87-132) are well-ordered and contain a three-stranded antiparallel sheet, where the last two strands form a hairpin. The relative spatial positioning of the disulfide cross-links demonstrates that the ordered region of AGRP(87-132) adopts the inhibitor cystine knot (ICK) fold previously identified for numerous invertebrate toxins. Interestingly, this may be the first example of a mammalian protein assigned to the ICK superfamily. The hairpin's turn region presents a triplet of residues (Arg-Phe-Phe) known to be essential for melanocortin receptor binding. The structure also suggests that AGRP possesses an additional melanocortin-receptor contact region within a loop formed by the first 16 residues of its C-terminal domain. This specific region shows little sequence homology to the corresponding region of the agouti protein, which is an MC1R antagonist involved in pigmentation. Consideration of these sequence differences, along with recent experiments on mutant and chimeric melanocortin receptors, allows us to postulate that this loop in the first 16 residues of its C-terminal domain confers AGRP's distinct selectivity for MC3R and MC4R.Obesity and associated disorders such as diabetes are now at epidemic levels in the United States and other developed countries (1, 2). An understanding at the molecular level of the normal processes governing energy homeostasis and weight regulation is therefore essential for developing a comprehensive understanding of these disorders and producing effective pharmaceutical treatments. Recent studies have demonstrated the key role played by brain melanocortin receptors (MCRs) in the regulation of energy homeostasis (3-6). Although MCRs are found in various tissues, these studies indicate that the specific receptors MC3R and MC4R are directly implicated in energy balance. All MCRs are G-protein-coupled receptors (GPCRs) that up-regulate the production of cAMP in the presence of small endogenous peptide agonists (7). These agonists are derived in vivo from the single pro-opiomelanocortin peptide (POMC) that is cleaved post-translationally to form the melanocortinstimulating hormones (MSHs) and the adrenocorticotropin hormone (ACTH). MCR function is also modulated by potent endogenous antagonists known as the agouti protein and the agouti-related protein (AGRP) that indeed may exert even greater control over MCR signaling than the peptide agonists (8-11). Relative to the small peptide agonists, these antagonists are larger in size and possess a five-dis...

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“…At first glance, no amino acid sequence similarity between Agouti/AGRP and ␣-MSH seems obvious. Careful comparison of Agouti and AGRP C-terminal sequences reveals, however, the presence of a conserved RFF motif that resembles the ␣-MSH pharmacophore HFRW (39). A loop of 8 residues flanked by two Cys residues and including the RFF triplet (AGRP residues 110 -117 and Agouti residues 115-122, respectively) is shown to be critical for both Agouti and AGRP antagonism at melanocortin receptors (39).…”

Section: Fine-tuning the Mechanism Of Agouti/agrp Actionmentioning

confidence: 99%

Agouti and Agouti-related Protein: Analogies and Contrasts

Dinulescu

Cone

2000

Journal of Biological Chemistry

124

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The discovery a decade ago of the murine agouti gene was intended to bring scientists a step closer to understanding the complexities of mammalian pigmentation. The first obesity gene was also uncovered in the process. What followed was an explosion of major discoveries in murine as well as human obesity and diabetes research. Recently, a new gene, the agouti-related protein (AGRP), 1 was discovered and found to share a striking similarity in structure and function with agouti, although their patterns of distribution are completely different. Identification of a hypothalamic melanocortin receptor, MC4-R, together with AGRP as central components of feeding behavior and metabolism has helped build a picture, albeit incomplete, of the neuronal pathways involved in energy homeostasis. This review will compare and contrast Agouti and AGRP structure and function and gene regulation and their interaction with melanocortin receptors (MC1-R and MC4-R) and suppressors (mahogany/mahoganoid). Agouti and Extension, a Brief Historyagouti and extension were first described several decades ago (1, 2) as the genetic loci that control the relative amount and distribution of eumelanin (brown/black) and phaeomelanin (red/yellow) pigments in the mammalian coat. extension encodes a member (MC1-R) (3) of the melanocortin receptors, a family of G s -coupled receptors, of which five isoforms are presently known (reviewed in Ref. 4). MC1-R is the melanocyte-stimulating hormone receptor expressed in melanocytes and has a physiological role in pigmentation (5). MC4-R is expressed mainly in the brain (6, 7) and has been implicated in the regulation of feeding behavior and metabolism (8). MC3-R is found primarily in the hypothalamic and limbic systems (9); however, no definitive function has been assigned to MC3-R as yet. Melanocortins such as ␣-melanocyte-stimulating hormone (␣-MSH) and adrenocorticotropic hormone (ACTH) are the natural ligands for this family of receptors (␣-MSH for MC1-, MC3-, MC4-, and MC5-R and ACTH for MC2-R). Melanocortins are cleaved from a larger polypeptidic precursor termed pro-opiomelanocortin that is produced in the pituitary gland, hypothalamus, brainstem, and peripheral sites such as skin.Agouti is a paracrine-signaling factor that is secreted by dermal papillae cells, adjacent to melanocytes, and acts within the hair follicle microenvironment to block melanocortin action at the MC1-R (10, 11). Binding of ␣-MSH to the receptor triggers elevation of cAMP levels and activation of tyrosinase, the rate-limiting enzyme of melanogenesis, and results in eumelanin production. In the presence of Agouti the opposite is true; eumelanin synthesis is shut down and the default pathway that has phaeomelanin as the final product is activated. There are now more than 20 dominant, recessive, and pseudoagouti alleles that have been identified in rodent, fox, and cattle, with interesting functional variations from species to species. In rodents agouti is expressed in skin only. In humans, however, agouti has a wider pattern of di...

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Molecular Interaction of Agouti Protein and Agouti-Related Protein with Human Melanocortin Receptors

Cited by 101 publications

References 22 publications

Molecular Determination of Agouti-Related Protein Binding to Human Melanocortin-4 Receptor

Molecular Determination of Agouti-Related Protein Binding to Human Melanocortin-4 Receptor

High-Resolution NMR Structure of the Chemically-Synthesized Melanocortin Receptor Binding Domain AGRP(87−132) of the Agouti-Related Protein^,

Agouti and Agouti-related Protein: Analogies and Contrasts

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Molecular Interaction of Agouti Protein and Agouti-Related Protein with Human Melanocortin Receptors

Cited by 101 publications

References 22 publications

Molecular Determination of Agouti-Related Protein Binding to Human Melanocortin-4 Receptor

Molecular Determination of Agouti-Related Protein Binding to Human Melanocortin-4 Receptor

High-Resolution NMR Structure of the Chemically-Synthesized Melanocortin Receptor Binding Domain AGRP(87−132) of the Agouti-Related Protein,

Agouti and Agouti-related Protein: Analogies and Contrasts

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High-Resolution NMR Structure of the Chemically-Synthesized Melanocortin Receptor Binding Domain AGRP(87−132) of the Agouti-Related Protein^,