Novel CaM-binding motif in its NudT9H domain contributes to temperature sensitivity of TRPM2
Novel CaM-binding motif in its NudT9H domain contributes to temperature sensitivity of TRPM2
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DOI：
10.1016/j.bbamcr.2018.12.010
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发表时间：
2019-07-01
影响因子：
5.1
通讯作者：
Tidow, Henning
中科院分区：
文献类型：
--
作者：
Gattkowski, Ellen;Johnsen, Anke;Tidow, Henning
TRPM2是一种非选择性的Ca2+渗透性阳离子通道，在细胞死亡中起作用，但也有助于多种免疫细胞功能。此外，TRPM2有助于体温的控制，并参与非有害热的感知和热趋向性。TRPM2受Ca2+、ADPR、2'-脱氧-ADPR、Ca2+-CaM和温度等多种因素调控。然而，TRPM2温度敏感性的分子基础以及调控因子之间的相互作用尚不清楚。在这里，我们在TRPM2独特的NudT9H结构域中发现了一个新的cam结合位点。使用多管齐下的生物物理方法，我们表明Ca2+-CaM与该位点的结合发生在温度为bb0 - 35℃的部分展开时，并防止进一步的热不稳定。结合膜片钳测量全长TRPM2，我们的结果表明，这个cam结合位点在TRPM2的温度敏感性中起作用。本文是克劳斯·海兹曼、约阿希姆·克雷布斯和雅克·海伊克主编的《ECS会议》特刊的一部分
TRPM2 is a non-selective, Ca2+-permeable cation channel, which plays a role in cell death but also contributes to diverse immune cell functions. In addition, TRPM2 contributes to the control of body temperature and is involved in perception of non-noxious heat and thermotaxis. TRPM2 is regulated by many factors including Ca2+, ADPR, 2'-deoxy-ADPR, Ca2+-CaM, and temperature. However, the molecular basis for the temperature sensitivity of TRPM2 as well as the interplay between the regulatory factors is still not understood.Here we identify a novel CaM-binding site in the unique NudT9H domain of TRPM2. Using a multipronged biophysical approach we show that binding of Ca2+-CaM to this site occurs upon partial unfolding at temperatures > 35 degrees C and prevents further thermal destabilization. In combination with patch-clamp measurements of full-length TRPM2 our results suggest a role of this CaM-binding site in the temperature sensitivity of TRPM2.This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech