Yu Bin, Millhauser Glenn L
Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA.
FEBS Lett. 2007 Dec 11;581(29):5561-5. doi: 10.1016/j.febslet.2007.10.062. Epub 2007 Nov 13.
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.
刺鼠信号蛋白（ASIP）及其同源物刺鼠相关蛋白（AgRP）作为反向激动剂，分别控制哺乳动物的色素沉着和代谢功能。核磁共振研究发现，这些蛋白质的C末端结构域呈现出一种与抑制剂胱氨酸结（ICK）一致的折叠结构，此前在无脊椎动物毒素中已鉴定出该结构。尽管这些结构研究表明ASIP和AgRP定义了一种新的哺乳动物蛋白质折叠类别，但关于ASIP的结果尚无定论。在这里，我们应用直接化学图谱法来确定ASIP中完整的二硫键连接。结果明确表明ASIP采用ICK折叠结构，从而支持了最近的进化结构功能分析，该分析提出ASIP和AgRP起源于一种共同的拮抗剂配体。
