Zeng Weizhong, Yuan Joseph P, Kim Min Seuk, Choi Young Jin, Huang Guo N, Worley Paul F, Muallem Shmuel
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Mol Cell. 2008 Nov 7;32(3):439-48. doi: 10.1016/j.molcel.2008.09.020.
The receptor-evoked Ca(2+) signal includes activation of the store-operated channels (SOCs) TRPCs and the Orais. Although both are gated by STIM1, it is not known how STIM1 gates the channels and whether STIM1 gates the TRPCs and Orais by the same mechanism. Here, we report the molecular mechanism by which STIM1 gates TRPC1, which involves interaction between two conserved, negatively charged aspartates in TRPC1((639)DD(640)) with the positively charged STIM1((684)KK(685)) in STIM1 polybasic domain. Charge swapping and functional analysis revealed that exact orientation of the charges on TRPC1 and STIM1 are required, but all positive-negative charge combinations on TRPC1 and STIM1, except STIM1((684)EE(685))+TRPC1((639)RR(640)), are functional as long as they are reciprocal, indicating that STIM1 gates TRPC1 by intermolecular electrostatic interaction. Similar gating was observed with TRPC3((697)DD(698)). STIM1 gates Orai1 by a different mechanism since the polybasic and S/P domains of STIM1 are not required for activation of Orai1 by STIM1.
受体诱发的Ca(2+)信号包括储存操纵性通道（SOCs）瞬时受体电位通道（TRPCs）和Orai通道的激活。尽管两者都由基质相互作用分子1（STIM1）门控，但尚不清楚STIM1如何门控这些通道，以及STIM1是否通过相同机制门控TRPCs和Orai通道。在此，我们报道了STIM1门控TRPC1的分子机制，该机制涉及TRPC1中两个保守的带负电荷的天冬氨酸（TRPC1((639)DD(640))）与STIM1多碱性结构域中带正电荷的STIM1((684)KK(685))之间的相互作用。电荷交换和功能分析表明，TRPC1和STIM1上电荷的精确取向是必需的，但TRPC1和STIM1上除了STIM1((684)EE(685))+TRPC1((639)RR(640))之外的所有正负电荷组合，只要它们是相互的，就具有功能，这表明STIM1通过分子间静电相互作用门控TRPC1。在TRPC3((697)DD(698))上观察到类似的门控作用。STIM1通过不同机制门控Orai1，因为STIM1的多碱性和S/P结构域对于STIM1激活Orai1并非必需。
