Melanocortin Receptor Binding Determinants in the Agouti Protein
The agouti protein plays an important role in the development of diabetes and obesity in rodents and has been shown to be a potent antagonist of melanocortin receptors. For this reason alanine-scanning mutagenesis was performed on the agouti protein carboxyl terminus to locate residues important for...
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Published in | Biochemistry (Easton) Vol. 37; no. 4; pp. 991 - 997 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Chemical Society
27.01.1998
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Subjects | |
Online Access | Get full text |
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Summary: | The agouti protein plays an important role in the development of diabetes and obesity in rodents and has been shown to be a potent antagonist of melanocortin receptors. For this reason alanine-scanning mutagenesis was performed on the agouti protein carboxyl terminus to locate residues important for melanocortin receptor binding inhibition. When agouti residues Arg116 and Phe118 are changed to alanine, very large decreases in agouti affinity for melanocortin receptor 1, 3, and 4 result. Mutation of Phe117 to alanine causes a similar increase in agouti K I app at melanocortin receptor 4. Substitution of agouti residue Asp108 with alanine results in large increases in K I app for all three melanocortin receptors examined. All of these residues are conserved in the agouti-related transcript, ART, whose expression is up-regulated in animal models of obesity. The three-dimensional structure of the agouti carboxyl terminus was modeled, and residues which decrease receptor binding by a factor of ≥15 when mutated to alanine localize to one side of the structure. These agouti variants with altered receptor selectivity may be useful in determining the role of melanocortin receptors in diabetes and obesity. |
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Bibliography: | K.G.M. is supported by a Wellcome Trust Senior Research Fellowship and the Health Research Council of New Zealand. istex:D704DBFFC28C5CBB36DB2C696FE750046FB3F4BD ark:/67375/TPS-GQTQ94Q7-1 |
ISSN: | 0006-2960 1520-4995 |
DOI: | 10.1021/bi971913h |