Structure of a TRPM2 channel in complex with Ca(2+) explains unique gating regulation.
Structure of a TRPM2 channel in complex with Ca(2+) explains unique gating regulation.
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DOI：
10.7554/elife.36409
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发表时间：
2018-05-10
期刊：
影响因子：
7.7
通讯作者：
Csanády L
中科院分区：
文献类型：
--
作者：
Zhang Z;Tóth B;Szollosi A;Chen J;Csanády L
瞬时受体电位melastatin 2（TRPM 2）是免疫细胞活化、胰岛素分泌和体温控制所需的Ca 2+渗透性阳离子通道。TRPM 2被胞质Ca 2+、磷脂酰肌醇-4，5-二磷酸和ADP核糖激活。在这里，我们提出了~3 μ m分辨率的电子冷冻显微结构的TRPM 2从Nematostella vectensis，63%的序列相似的人TRPM 2，在钙离子结合的封闭状态。与其他TRPM通道相比，TRPM 2具有与其功能相关的独特结构特征。孔更大且带更多负电荷，与其高Ca 2+选择性和更大电导一致。胞内Ca 2+结合位点连接到孔和胞质溶胶，解释了TRPM 2活性对细胞内和细胞外Ca 2+的不寻常依赖性。此外，后过滤基序的缺乏可能是人TRPM 2快速失活的原因。总之，我们的cryo-EM和电生理学研究提供了对TRPM 2独特门控机制的分子理解。
Transient receptor potential melastatin 2 (TRPM2) is a Ca2+-permeable cation channel required for immune cell activation, insulin secretion, and body heat control. TRPM2 is activated by cytosolic Ca2+, phosphatidyl-inositol-4,5-bisphosphate and ADP ribose. Here, we present the ~3 Å resolution electron cryo-microscopic structure of TRPM2 from Nematostella vectensis, 63% similar in sequence to human TRPM2, in the Ca2+-bound closed state. Compared to other TRPM channels, TRPM2 exhibits unique structural features that correlate with its function. The pore is larger and more negatively charged, consistent with its high Ca2+ selectivity and larger conductance. The intracellular Ca2+ binding sites are connected to the pore and cytosol, explaining the unusual dependence of TRPM2 activity on intra- and extracellular Ca2+. In addition, the absence of a post-filter motif is likely the cause of the rapid inactivation of human TRPM2. Together, our cryo-EM and electrophysiology studies provide a molecular understanding of the unique gating mechanism of TRPM2.