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Chemical disulfide mapping identifies an inhibitor cystine knot in the agouti signaling protein
Author(s) -
Yu Bin,
Millhauser Glenn L.
Publication year - 2007
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2007.10.062
Subject(s) - antagonist , cystine , disulfide bond , chemistry , biology , microbiology and biotechnology , biochemistry , computational biology , genetics , receptor , enzyme , cysteine
The agouti signaling protein (ASIP) and its homolog, the agouti‐related protein (AgRP), act as inverse agonists that control, respectively, pigmentation and metabolic function in mammals. NMR investigations find that the C‐terminal domains of these proteins adopt a fold consistent with an inhibitor cystine knot (ICK), previously identified in invertebrate toxins. Although these structural studies suggest that ASIP and AgRP define a new mammalian protein fold class, the results with ASIP are inconclusive. Here, we apply direct chemical mapping to determine the complete set of disulfide linkages in ASIP. The results demonstrate unequivocally that ASIP adopts the ICK fold and thereby supports a recent evolution structure function analysis, which proposes that ASIP and AgRP arose from a common antagonist ligand.