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Molecular interaction of Agouti protein and Agouti-related protein with human melanocortin receptors.

Molecular interaction of Agouti protein and Agouti-related protein with human melanocortin receptors.

Authors :
Tota MR
Smith TS
Mao C
MacNeil T
Mosley RT
Van der Ploeg LH
Fong TM
Source :
Biochemistry [Biochemistry] 1999 Jan 19; Vol. 38 (3), pp. 897-904.
Publication Year :
1999

Abstract

Agouti protein and the Agouti-related protein (AGRP) are antagonists of the melanocortin-3 receptor and melanocortin-4 receptor. Both proteins contain 10 cysteines in the C-terminal domain arranged in five disulfide bonds. One possible arrangement of the disulfide bonds predicts an octapeptide loop, and the chemical properties of four residues within this loop (residues 111-114 in human AGRP) bear striking resemblance to those of several melanocortin peptides, including alpha-MSH, MT-II, and SHU-9119. We showed that cyclic synthetic octapeptides based on the sequence of this loop from Agouti protein or human AGRP are functional antagonists of the human melanocortin-4 receptor. All peptides had a lower affinity for the melanocortin-3 receptor than for the melanocortin-4 receptor. Substitution of serines for cysteines resulted in linear peptides which had reduced binding affinities for both receptors. Mutational analysis of human AGRP indicated that its C-terminal domain is functionally equivalent to the intact human AGRP. The RFF111-113 triplet appears to be the most critical portion of AGRP in determining the binding affinity for both melanocortin-3 and melanocortin-4 receptors. These data strongly suggest that the loop defined by Cys-110 and Cys-117 is critical in determining the antagonist activity of human AGRP. Our data provide indirect evidence for the suggestion that the Cys-110 to Cys-117 octapeptide loop of human AGRP mimics the conformation of alpha-MSH, MT-II, and SHU-9119.

Details

Language :
English
ISSN :
0006-2960
Volume :
38
Issue :
3
Database :
MEDLINE
Journal :
Biochemistry
Publication Type :
Academic Journal
Accession number :
9893984
Full Text :
https://doi.org/10.1021/bi9815602