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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.
- 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.
- Subjects :
- Agouti Signaling Protein
Agouti-Related Protein
Amino Acid Sequence
Animals
DNA Mutational Analysis
Humans
Mice
Models, Molecular
Molecular Sequence Data
Oligopeptides pharmacology
Peptides, Cyclic pharmacology
Protein Binding drug effects
Proteins genetics
Proteins pharmacology
Receptor, Melanocortin, Type 4
Receptors, Peptide antagonists & inhibitors
Sequence Alignment
Sequence Homology, Amino Acid
alpha-MSH analogs & derivatives
alpha-MSH antagonists & inhibitors
alpha-MSH metabolism
Intercellular Signaling Peptides and Proteins
Proteins metabolism
Receptors, Peptide metabolism
Subjects
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