{PDOC60024} {PS60024; AGOUTI_1} {PS51150; AGOUTI_2} {BEGIN} *************************************** * 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 alpha-melanocyte stimulating hormone (alpha-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 beta sheet, where the last two strands form a beta hairpin (see ). 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. -Conserved pattern: C-x(6)-C-x(6)-C-C-x(2)-C-x(2)-C-x-C-x(6)-C-x-C-x(6,9)-C [The 10 C's are involved in disulfide bonds] -Sequences known to belong to this class detected by the pattern: ALL. -Other sequence(s) detected in Swiss-Prot: NONE. -Sequences known to belong to this class detected by the profile: ALL. -Other sequence(s) detected in Swiss-Prot: NONE. -Expert(s) to contact by email: Ramakumar S.; ramak@physics.iisc.ernet.in -Last update: October 2005 / First entry. [ 1] Voisey J., Kelly G., Van Daal A. "Agouti signal protein regulation in human melanoma cells." Pigment Cell Res. 16:65-71(2003). PubMed=12519127 [ 2] McNulty J.C., Jackson P.J., Thompson D.A., Chai B., Gantz I., Barsh G.S., Dawson P.E., Millhauser G.L. "Structures of the agouti signaling protein." J. Mol. Biol. 346:1059-1070(2005). PubMed=15701517; DOI=10.1016/j.jmb.2004.12.030 [ 3] McNulty J.C., Thompson D.A., Bolin K.A., Wilken J., Barsh G.S., Millhauser G.L. "High-resolution NMR structure of the chemically-synthesized melanocortin receptor binding domain AGRP(87-132) of the agouti-related protein." Biochemistry 40:15520-15527(2001). PubMed=11747427; DOI=10.1021/bi0117192 [E1] https://bioserv.cbs.cnrs.fr -------------------------------------------------------------------------------- PROSITE is copyrighted by the SIB Swiss Institute of Bioinformatics and distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND 4.0) License, see https://prosite.expasy.org/prosite_license.html -------------------------------------------------------------------------------- {END}