Structural and molecular evolutionary analysis of Agouti and Agouti-related proteins
Structural and molecular evolutionary analysis of Agouti and Agouti-related proteins
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DOI：
10.1016/j.chembiol.2006.10.006
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发表时间：
2006-12-01
影响因子：
--
通讯作者：
Millhauser, Glenn L.
中科院分区：
文献类型：
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作者：
Jackson, Pilgrim J.;Douglas, Nick R.;Millhauser, Glenn L.
Agouti (ASIP) 和 Agouti 相关蛋白 (AgRP) 是黑皮质素受体的内源性拮抗剂，分别在色素沉着和能量平衡的调节中发挥关键作用，并且起源于脊椎动物进化早期的共同祖先基因。 ASIP 的 N 端结构域通过与辅助受体结合来促进拮抗作用，但在这里我们表明 AgRP 的 N 端结构域具有相反的作用，并充当负调节拮抗剂功能的前结构域。计算分析揭示了 ASIP 和 AgRP C 端域的进化约束模式相似，但 N 端域之间存在根本差异。这些研究揭示了色素沉着调节和体重之间的关系，并说明了进化结构功能分析如何揭示旁系同源基因产物的独特和常见的作用机制。
Agouti (ASIP) and Agouti-related protein (AgRP) are endogenous antagonists of melanocortin receptors that play critical roles in the regulation of pigmentation and energy balance, respectively, and which arose from a common ancestral gene early in vertebrate evolution. The N-terminal domain of ASIP facilitates antagonism by binding to an accessory receptor, but here we show that the N-terminal domain of AgRP has the opposite effect and acts as a prodomain that negatively regulates antagonist function. Computational analysis reveals similar patterns of evolutionary constraint in the ASIP and AgRP C-terminal domains, but fundamental differences between the N-terminal domains. These studies shed light on the relationships between regulation of pigmentation and body weight, and they illustrate how evolutionary structure function analysis can reveal both unique and common mechanisms of action for paralogous gene products.