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Structural and molecular evolutionary analysis of Agouti and Agouti-related proteins.

Authors
  • Pj, Jackson
  • Nr, Douglas
  • B, Chai
  • J, Binkley
  • A, Sidow
  • Gs, Barsh
  • Glenn Millhauser
Type
Published Article
Journal
Chemistry & Biology
Publisher
Elsevier
Volume
13
Issue
12
Pages
1297–1305
Source
UCSC Aging biomedical-ucsc
License
Unknown

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.

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