title: Structural and molecular evolutionary analysis of Agouti and Agouti-related proteins.
abstract: Agouti (ASIP) and Agouti-related protein (AgRP) are endogenous antagonists of melanocortin receptors that play critical roles in the regulation of pigmentation and energy balance, respectively, and which arose from a common ancestral gene early in vertebrate evolution. The N-terminal domain of ASIP facilitates antagonism by binding to an accessory receptor, but here we show that the N-terminal domain of AgRP has the opposite effect and acts as a prodomain that negatively regulates antagonist function. Computational analysis reveals similar patterns of evolutionary constraint in the ASIP and AgRP C-terminal domains, but fundamental differences between the N-terminal domains. These studies shed light on the relationships between regulation of pigmentation and body weight, and they illustrate how evolutionary structure function analysis can reveal both unique and common mechanisms of action for paralogous gene products.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064, USA.
authors.forename: Pilgrim J
authors.initials: PJ
authors.lastname: Jackson
authors.forename: Nick R
authors.initials: NR
authors.lastname: Douglas
authors.forename: Biaoxin
authors.initials: B
authors.lastname: Chai
authors.forename: Jonathan
authors.initials: J
authors.lastname: Binkley
authors.forename: Arend
authors.initials: A
authors.lastname: Sidow
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Barsh
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Millhauser
mesh_terms: D054366:Agouti Signaling Protein; D054369:Agouti-Related Protein; D000595:Amino Acid Sequence; D000818:Animals; D019295:Computational Biology; D019143:Evolution, Molecular; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016415:Sequence Alignment
chemical_list: C515198:AGRP protein, human; D054366:Agouti Signaling Protein; D054369:Agouti-Related Protein; D036341:Intercellular Signaling Peptides and Proteins