Structures of the Agouti Signaling Protein

McNulty, Joseph C.; Jackson, Pilgrim J.; Thompson, Darren A.; Chai, Biaoxin; Gantz, Ira; Barsh, Gregory S.; Dawson, Philip E.; Millhauser, Glenn L.

doi:10.1016/j.jmb.2004.12.030

Cited by 77 publications

(129 citation statements)

References 53 publications

(60 reference statements)

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“…This specific sequence corresponds to the double-mutant ASIP(80-132, Q115Y, S124Y) in which the two X → Y mutations are included to enhance folding and stability. Referred to as ASIP-YY, this protein exhibits MC1R affinity and selectivity equivalent to that of wild-type ASIP (16).…”

Section: Methodsmentioning

confidence: 99%

“…To further test the role of protein trafficking and eumelanosome formation in influencing melanoma drug sensitivity, we used an alternative method to moderate both processes. The binding of the melanocyte-stimulating hormone (MSH) to the MC1R on the cell surface of melanocytes has been shown to increase mature eumelanosome number, whereas binding of the antagonist agouti-signaling peptide (ASIP) to the receptor causes a decrease in mature eumelanosome formation (16)(17)(18). MSH binding to the MC1R has also been shown to influence the trafficking of the catalase protein (19).…”

Section: Chemosensitivity Is Up-regulated or Down-regulated By Receptmentioning

confidence: 99%

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Targeting protein-trafficking pathways alters melanoma treatment sensitivity

Huang

Chinen

Chang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Protein-trafficking pathways are targeted here in human melanoma cells using methods independent of oncogene mutational status, and the ability to up-regulate and down-regulate tumor treatment sensitivity is demonstrated. Sensitivity of melanoma cells to cis-diaminedichloroplatinum II (cDDP, cis-platin), carboplatin, dacarbazine, or temozolomide together with velaparib, an inhibitor of poly (ADP ribose) polymerase 1, is increased by up to 10-fold by targeting genes that regulate both protein trafficking and the formation of melanosomes, intracellular organelles unique to melanocytes and melanoma cells. Melanoma cells depleted of either of the proteintrafficking regulators vacuolar protein sorting 33A protein (VPS33A) or cappuccino protein (CNO) have increased nuclear localization of cDDP, increased nuclear DNA damage by platination, and increased apoptosis, resulting in increased treatment sensitivity. Depleted cells also exhibit a decreased proportion of intracellular, mature melanosomes compared with undepleted cells. Modulation of protein trafficking via cell-surface signaling by binding the melanocortin 1 receptor with the antagonist agouti-signaling protein decreased the proportion of mature melanosomes formed and increased cDDP sensitivity, whereas receptor binding with the agonist melanocytestimulating hormone resulted in an increased proportion of mature melanosomes formed and in decreased sensitivity (i.e., increased resistance) to cDDP. Mutation of the protein-trafficking gene Hps6, known to impair the formation of mature melanosomes, also increased cDDP sensitivity. Together, these results indicate that targeting protein-trafficking molecules markedly increases melanoma treatment sensitivity and influences the degree of melanosomes available for sequestration of therapeutic agents.

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Section: Methodsmentioning

confidence: 99%

Section: Chemosensitivity Is Up-regulated or Down-regulated By Receptmentioning

confidence: 99%

Targeting protein-trafficking pathways alters melanoma treatment sensitivity

Huang

Chinen

Chang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…The ASIP protein sequence contains a secretion signal, a basic amino-terminal domain, a proline stretch and a cysteine-rich carboxy-terminal domain that folds in a characteristic knot structure. The cysteine-rich domain is responsible for melanocortin binding activity in vitro (Kiefer et al, 1997;McNulty et al, 2005). A large number of alleles have been described at the Agouti locus in mice, with most having been characterized at the DNA level (e.g.…”

Section: Introductionmentioning

confidence: 99%

Coat colours in the Massese sheep breed are associated with mutations in the agouti signalling protein (ASIP) and melanocortin 1 receptor (MC1R) genes

Fontanesi

Dall’Olio

Beretti

et al. 2011

Animal

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Massese is an Italian dairy sheep breed characterized by animals with black skin and horns and black or apparent grey hairs. Owing to the presence of these two coat colour types, this breed can be considered an interesting model to evaluate the effects of coat colour gene polymorphisms on this phenotypic trait. Two main loci have been already shown to affect coat colour in sheep: Agouti and Extension coding for the agouti signalling protein (ASIP) and melanocortin 1 receptor (MC1R) genes, respectively. The Agouti locus is affected by a large duplication including the ASIP gene that may determine the Agouti white and tan allele (A Wt ). Other disrupting or partially inactivating mutations have been identified in exon 2 (a deletion of 5 bp, D 5 ; and a deletion of 9 bp, D 9 ) and in exon 4 (g.5172T.A, p.C126S) of the ASIP gene. Three missense mutations in the sheep MC1R gene cause the dominant black E D allele (p.M73K and p.D121N) and the putative recessive e allele (p.R67C). Here, we analysed these ASIP and MC1R mutations in 161 Massese sheep collected from four flocks. The presence of one duplicated copy allele including the ASIP gene was associated with grey coat colour (P 5 9.4E-30). Almost all animals with a duplicated copy allele (37 out of 41) showed uniform apparent grey hair and almost all animals without a duplicated allele (117 out of 120) were completely black. Different forms of duplicated alleles were identified in Massese sheep including, in almost all cases, copies with exon 2 disrupting or partially inactivating mutations making these alleles different from the A Wt allele. A few exceptions were observed in the association between ASIP polymorphisms and coat colour: three grey sheep did not carry any duplicated copy allele and four black animals carried a duplicated copy allele. Of the latter four sheep, two carried the E D allele of the MC1R gene that may be the cause of their black coat colour. The coat colour of all other black animals may be determined by non-functional ASIP alleles (non-agouti alleles, A a ) and in a few cases by the E D Extension allele. At least three frequent ASIP haplotypes ([D 5 :g.5172T], [N:g.5172A] and [D 5 :g.5172A]) were detected (organized into six different diplotypes). In conclusion, the results indicated that coat colours in the Massese sheep breed are mainly derived by combining ASIP and MC1R mutations.

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“…Three functional domains have been identified in ASIP: the C-terminal loop, the active loop and the N-terminal loop. The active loop contains the highly conserved RFF motif which is essential in recognition, binding and inverse agonist function and makes direct contact with the receptor in the transmembrane pocket [49][50][51]. The site of contact is thought to be partially overlapping the site for a-MSH [52,53].…”

Section: Discussionmentioning

confidence: 99%

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)

et al. 2014

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a b s t r a c tThe melanocortin-1 receptor (MC1R) is a key regulator of mammalian pigmentation. Melanism in the grey squirrel is associated with an eight amino acid deletion in the mutant melanocortin-1 receptor with 24 base pair deletion (MC1RD24) variant. We demonstrate that the MC1RD24 exhibits a higher basal activity than the wildtype MC1R (MC1R-wt). We demonstrate that agouti signalling protein (ASIP) is an inverse agonist to the MC1R-wt but is an agonist to the MC1RD24. We conclude that the deletion in the MC1RD24 leads to a receptor with a high basal activity which is further activated by ASIP. This is the first report of ASIP acting as an agonist to MC1R.

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Structures of the Agouti Signaling Protein

Cited by 77 publications

References 53 publications

Targeting protein-trafficking pathways alters melanoma treatment sensitivity

Targeting protein-trafficking pathways alters melanoma treatment sensitivity

Coat colours in the Massese sheep breed are associated with mutations in the agouti signalling protein (ASIP) and melanocortin 1 receptor (MC1R) genes

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)

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