The LisH Motif of Muskelin Is Crucial for Oligomerization and Governs Intracellular Localization
The LisH Motif of Muskelin Is Crucial for Oligomerization and Governs Intracellular Localization
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DOI：
10.1016/j.str.2014.11.016
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发表时间：
2015-02-03
期刊：
影响因子：
5.7
通讯作者：
Schindelin, Hermann
中科院分区：
文献类型：
--
作者：
Delto, Carolyn F.;Heisler, Frank F.;Schindelin, Hermann
神经元通过平衡进出质膜的运输来调节表面受体的数量，以调整其信号传导特性。最近，muskelin 蛋白被确定为指导含有 α1 亚基的 GABA(A) 受体转运的关键因子。在这里，我们展示了 muskelin 的晶体结构，包括其 N 末端盘状蛋白结构域和 Lis1 同源 (LisH) 基序。该分子结晶为二聚体，其 LisH 基序专门介导寡聚化。我们随后的生化分析证实 LisH 基序在 muskelin 中充当二聚化元件。与分子间头尾相互作用一起，LisH 依赖性二聚化是组装 muskelin 四聚体所必需的。有趣的是，我们的细胞研究表明，这种二聚化的丧失会导致 muskelin 从细胞质到细胞核的完全重新分配，并损害 muskelin 在 GABAA 受体转运中的功能。这些研究表明 LisH 依赖性二聚化是 muskelin 功能的关键因素。
Neurons regulate the number of surface receptors by balancing the transport to and from the plasma membrane to adjust their signaling properties. The protein muskelin was recently identified as a key factor guiding the transport of alpha 1 subunit-containing GABA(A) receptors. Here we present the crystal structure of muskelin, comprising its N-terminal discoidin domain and Lis1-homology (LisH) motif. The molecule crystallized as a dimer with the LisH motif exclusively mediating oligomerization. Our subsequent biochemical analyses confirmed that the LisH motif acts as a dimerization element in muskelin. Together with an intermolecular head-to-tail interaction, the LisH-dependent dimerization is required to assemble a muskelin tetramer. Intriguingly, our cellular studies revealed that the loss of this dimerization results in a complete redistribution of muskelin from the cytoplasm to the nucleus and impairs muskelin's function in GABAA receptor transport. These studies demonstrate that the LisH-dependent dimerization is a crucial factor for muskelin function.