The synaptic acetylcholinesterase tetramer assembles around a polyproline II helix
The synaptic acetylcholinesterase tetramer assembles around a polyproline II helix
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DOI：
10.1038/sj.emboj.7600425
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发表时间：
2004-11-10
期刊：
影响因子：
11.4
通讯作者：
Silman, I
中科院分区：
文献类型：
--
作者：
Dvir, H;Harel, M;Silman, I
乙酰胆碱酯酶（AChE）在脊椎动物肌肉和大脑中的功能定位取决于色氨酸两亲四聚化（WAT）序列在其主要剪接变体(T)的c端与锚定蛋白、胶原（ColQ）和富含脯氨酸的膜锚定蛋白的富含脯氨酸的附着结构域（PRAD）的相互作用。WAT/PRAD配合物的晶体结构揭示了一种新的超螺旋结构，其中四个平行的WAT链围绕一个反平行的左旋PRAD螺旋形成一个左旋超螺旋，类似于聚脯氨酸II。WAT卷曲线圈具有WWW基序，可与PRAD进行重复疏水堆叠和氢键相互作用。WAT链由类似于PRAD周围的4倍螺旋轴连接。每个WAT产生相似但独特的相互作用，与AChE四聚体亚基和ColQ之间的二硫键的不对称模式一致。ColQ中的P59Q突变导致先天性终板AChE缺乏，并且位于PRAD内，破坏了关键的WAT - WAT和WAT - PRAD相互作用。提出了突触AChE(T)四聚体的模型。
Functional localization of acetylcholinesterase (AChE) in vertebrate muscle and brain depends on interaction of the tryptophan amphiphilic tetramerization (WAT) sequence, at the C-terminus of its major splice variant (T), with a proline-rich attachment domain (PRAD), of the anchoring proteins, collagenous (ColQ) and proline-rich membrane anchor. The crystal structure of the WAT/PRAD complex reveals a novel supercoil structure in which four parallel WAT chains form a left-handed superhelix around an antiparallel left-handed PRAD helix resembling polyproline II. The WAT coiled coils possess a WWW motif making repetitive hydrophobic stacking and hydrogen-bond interactions with the PRAD. The WAT chains are related by an similar to4-fold screw axis around the PRAD. Each WAT makes similar but unique interactions, consistent with an asymmetric pattern of disulfide linkages between the AChE tetramer subunits and ColQ. The P59Q mutation in ColQ, which causes congenital endplate AChE deficiency, and is located within the PRAD, disrupts crucial WAT - WAT and WAT - PRAD interactions. A model is proposed for the synaptic AChE(T) tetramer.