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J Biol Chem, Vol. 274, Issue 20, 14100-14106, May 14, 1999

Contribution of Melanocortin Receptor Exoloops to Agouti-related Protein Binding

Ying-kui Yang, Chris J. Dickinson^§, Qun Zeng^¶, Ji-Yao Li, Darren A. Thompson, and Ira Gantz^¶

From the  Departments of General Surgery, University of Michigan Medical School and ^¶ Ann Arbor Veterans Administration Hospital, Ann Arbor, Michigan 48109, ^§ Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan 48109, and  Gryphon Sciences, South San Francisco, California 94080

Agouti-related protein (AGRP) is an endogenous antagonist of melanocortin action that functions in the hypothalamic control of feeding behavior. Although previous studies have shown that AGRP binds three of the five known subtypes of melanocortin receptor, the receptor domains participating in binding and the molecular interactions involved are presently unknown. The present studies were designed to examine the contribution of extracytoplasmic domains of the melanocortin-4 receptor (MC4R) to AGRP binding by making chimerical receptor constructs of the human melanocortin-1 receptor (MC1R; a receptor that is not inhibited by AGRP) and the human MC4R (a receptor that is potently inhibited by AGRP). Substitutions of the extracytoplasmic NH₂ terminus and the first extracytoplasmic loop (exoloop) of the MC4R with homologous domains of the MC1R had no effect on AGRP (87-132) binding affinity or inhibitory activity (the ability to inhibit melanocortin-stimulated cAMP generation). In contrast, cassette substitutions of exoloops 2 and 3 of the MC4R with the homologous exoloops of the MC1R resulted in a substantial loss of AGRP binding affinity and inhibitory activity. Conversely, the exchange of exoloops 2 and 3 of the MC1R with the homologous exoloops of the MC4R was found to confer AGRP binding and inhibitory activity to the basic structure of the MC1R. Importantly, these substitutions did not affect the ability of the -melanocyte stimulating hormone analogue [Nle⁴,D-Phe⁷] melanocyte stimulating hormone to bind or activate the chimeric receptors. These data indicate that exoloops 2 and 3 of the melanocortin receptors are important for AGRP binding.

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