PROSITE documentation PDOC60024

Agouti domain signature and profile

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.