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PROSITE documentation PDOC60024 [for PROSITE entry PS51150]

Agouti domain signature and profile





Description

The agouti signaling protein (ASIP or the agouti protein) and its neuropeptide homolog the agouti-related protein (AgRP) are paracrine signaling molecules that act as inverse agonists at distinct subsets of melanocortin receptors. ASIP antagonizes the binding of α-melanocyte stimulating hormone (α-MSH) to melanocortin 1 receptor (MC1R), switching melanin synthesis from eumelanin (black/brown) to phaeomelanin (red/yellow). The effect of ASIP on pigment type-switching is responsible for a variety of coat color patterns accross a broad range of mammalian species. AgRP is involved in energy balance and acts normally at the MC3R and MC4R to control body weight regulation and metabolism [1,2].

Sequence similarity between ASIP and AgRP is confined to their Cys-rich C-terminal domains, which are also responsible for melanocortin receptor binding activity in vitro. Approximately 40 residues in length, there are ten cysteine residues in the C-terminal domain that form a network of five disulfide bonds (see the schematic representation below). The agouti C-terminal domain contains a three-stranded antiparallel β sheet, where the last two strands form a β hairpin (see <PDB:1HYK>). The hairpin's turn region presents a triplet of residues (Arg-Phe-Phe) known to be essential for melanocortin receptor binding. The agouti C-terminal domain adopts the inhibitor cystine knot (ICK) or knottin fold identified in numerous invertebrate toxins [2,3,E1].

                                  +---------------------+
                    +---------+   |        +---+        |
                    #         #   |        #   #        |
                    CxxxxCxxxCCxxxCxxxCxxxxCxxxCxxxCxxxxC
                         |   |        |            |
                         +---|--------+            |
                             +---------------------+
'C': conserved cysteine involved in a disulfide bond.
'#': positions of the cysteine, which are not involved in knottin scaffold

Our pattern and profile for the agouti domain cover the 10 cysteines involved in disulfide bonds.

Expert(s) to contact by email:

Ramakumar S.

Last update:

October 2005 / First entry.

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Technical section

PROSITE methods (with tools and information) covered by this documentation:

AGOUTI_2, PS51150; Agouti domain profile  (MATRIX)

AGOUTI_1, PS60024; Agouti domain signature  (PATTERN)


References

1AuthorsVoisey J. Kelly G. Van Daal A.
TitleAgouti signal protein regulation in human melanoma cells.
SourcePigment Cell Res. 16:65-71(2003).
PubMed ID12519127

2AuthorsMcNulty J.C. Jackson P.J. Thompson D.A. Chai B. Gantz I. Barsh G.S. Dawson P.E. Millhauser G.L.
TitleStructures of the agouti signaling protein.
SourceJ. Mol. Biol. 346:1059-1070(2005).
PubMed ID15701517
DOI10.1016/j.jmb.2004.12.030

3AuthorsMcNulty J.C. Thompson D.A. Bolin K.A. Wilken J. Barsh G.S. Millhauser G.L.
TitleHigh-resolution NMR structure of the chemically-synthesized melanocortin receptor binding domain AGRP(87-132) of the agouti-related protein.
SourceBiochemistry 40:15520-15527(2001).
PubMed ID11747427
DOI10.1021/bi0117192

E1Sourcehttp://knottin.cbs.cnrs.fr



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