Loop-swapped chimeras of the agouti-related protein and the agouti signaling protein identify contacts required for melanocortin 1 receptor selectivity and antagonism.
Loop-swapped chimeras of the agouti-related protein and the agouti signaling protein identify contacts required for melanocortin 1 receptor selectivity and antagonism.
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DOI：
10.1016/j.jmb.2010.08.054
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发表时间：
2010-11-19
影响因子：
5.6
通讯作者：
Millhauser GL
中科院分区：
文献类型：
--
作者：
Patel MP;Cribb Fabersunne CS;Yang YK;Kaelin CB;Barsh GS;Millhauser GL
聚集相关蛋白（AgRP）和聚集信号传导蛋白（ASIP）是分别在能量平衡和色素沉着中起关键作用的同源物，通过在它们的同源黑皮质素受体（MCR）上作为拮抗配体起作用。信号传导特异性部分地通过配体的富含半胱氨酸的羧基末端结构域的改变所带来的受体结合选择性来介导。AgRP以高亲和力结合黑皮质素3和黑皮质素4受体（MC 3R和MC 4 R），但不结合MC 1 R，而ASIP以高亲和力结合所有三种受体。这项工作探讨了受体选择性的结构基础，通过研究嵌合蛋白之间的交换环ASIP和AgRP富含半胱氨酸的结构域。结合数据表明，MC 4 R响应于所有嵌合体，因此对总环变化具有高度耐受性。相比之下，MC 1 R主要响应于那些序列接近野生型ASIP的嵌合体。结合和功能数据的进一步分析表明，ASIP C-末端环-由最终二硫键封闭的六个氨基酸片段-对于高亲和力MC 1 R结合和反向激动作用至关重要。与先前发表的分子模型的比较表明，该环通过一系列关键的疏水相互作用与MC 1 R的第一个细胞外环（EC 1）接触。
Agouti related protein (AgRP) and agouti signaling protein (ASIP) are homologs that play critical roles in energy balance and pigmentation, respectively, by functioning as antagonistic ligands at their cognate melanocortin receptors (MCRs). Signaling specificity is mediated in part through receptor binding selectivity brought about by alterations in the cysteine-rich carboxy-terminal domains of the ligands. AgRP binds with high affinity to the melanocortin 3 and melanocortin 4 receptors (MC3R and MC4R), but not to the MC1R, whereas ASIP binds with high affinity to all three receptors. This work explores the structural basis for receptor selectivity by studying chimeric proteins developed by interchanging loops between the cysteine-rich domains of ASIP and AgRP. Binding data demonstrate that MC4R responds to all chimeras, and is therefore highly tolerant of gross loop changes. By contrast, MC1R responds primarily to those chimeras with sequence close to wild type ASIP. Further analysis of binding and functional data suggests that the ASIP C-terminal loop – a six amino acid segment closed by the final disulfide bond – is essential for high affinity MC1R binding and inverse agonism. Comparison with previously published molecular models suggests that this loop makes contact to the first extracellular loop (EC1) of MC1R through a series of key hydrophobic interactions.
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影响因子：
--
作者：
Jackson, Pilgrim J.;Douglas, Nick R.;Millhauser, Glenn L.
通讯作者：
Millhauser, Glenn L.
影响因子：
3
作者：
Jackson, PJ;Yu, B;Millhauser, GL
通讯作者：
Millhauser, GL
影响因子：
2.9
作者：
Kiefer, LL;Veal, JM;Wilkinson, WO
通讯作者：
Wilkinson, WO
影响因子：
4.3
作者：
Le Pape, Elodie;Wakamatsu, Kazumasa;Hearing, Vincent J.
通讯作者：
Hearing, Vincent J.
影响因子：
4.8
作者：
Ho, GY;MacKenzie, RG
通讯作者：
MacKenzie, RG