Activation Stoichiometry and Pore Architecture of TRPA1 Probed with Channel Concatemers.
Activation Stoichiometry and Pore Architecture of TRPA1 Probed with Channel Concatemers.
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DOI：
10.1038/s41598-018-35435-y
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发表时间：
2018-11-20
影响因子：
4.6
通讯作者：
Liman ER
中科院分区：
文献类型：
--
作者：
Ye W;Tu YH;Cooper AJ;Zhang Z;Katritch V;Liman ER
伤害感受器离子通道TRPA1检测广泛的危险化学物质，包括反应性亲电体，如肉桂醛，其门控通道允许Na+和Ca2+进入。TRPA1组装为四聚体，具有中心孔，其中天冬氨酸残基（D918）决定Ca2+渗透性。在这里，我们报告说，在这个位置，D918 H，组氨酸的引入，使TRPA1通道敏感的阻断纳摩尔浓度的Zn 2+，可用于功能标签亚基的多联体。具有增加的D918H亚基数目的多联体显示对Zn 2+抑制的增加的敏感性，表明四聚体的位置918处的四个侧链直接配位Zn 2+和其它渗透性二价阳离子。在已发表的TRPA1结构中，这需要孔区域的重排，这可能代表通道的真正开放状态。当只有两个亚基含有完整的配体结合位点时，含有突变为对反应性亲电体（C622S）不敏感的亚基的串联通道可以被肉桂醛激活。四种可能的亚基中只有两种配体激活可能代表了快速可靠地检测有毒化学物质的最佳策略。
The nociceptor ion channel TRPA1 detects a wide range of hazardous chemicals, including reactive electrophiles such as cinnamaldehyde, which gate the channel allowing Na+ and Ca2+ entry. TRPA1 assembles as a tetramer, with a central pore within which an aspartate residue (D918) determines Ca2+ permeability. Here, we report that introduction of histidine at this position, D918H, makes TRPA1 channels sensitive to block by nanomolar concentration of Zn2+ and can be used to functionally tag subunits in concatemers. Concatemers with increasing numbers of D918H subunits display increasing sensitivity to Zn2+ inhibition, indicating that the four side chains at position 918 of the tetramer directly coordinate Zn2+ and other permeating divalent cations. In the published structure of TRPA1, this requires a rearrangement of the pore region which may represent the true open state of the channel. Concatemeric channels containing subunits mutated to be insensitive to reactive electrophiles (C622S) could be activated by cinnamaldehyde when as few as two subunits contained intact ligand binding sites. Activation upon liganding of just two of the four possible subunits may represent an optimal strategy to rapidly and reliably detect noxious chemicals.
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