The Short N-terminal Domains of STIM1 and STIM2 Control the Activation Kinetics of Orai1 Channels
The Short N-terminal Domains of STIM1 and STIM2 Control the Activation Kinetics of Orai1 Channels
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DOI：
10.1074/jbc.c109.010900
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发表时间：
2009-07-17
影响因子：
4.8
通讯作者：
Soboloff, Jonathan
中科院分区：
文献类型：
--
作者：
Zhou, Yandong;Mancarella, Salvatore;Soboloff, Jonathan
STIM1和STIM2是动态跨膜内质网Ca2+传感器，直接偶联激活质膜Orai Ca2+进入通道。尽管有广泛的序列同源性，但STIM蛋白在功能上是不同的。我们发现STIM1和STIM2的短可变n端随机线圈序列赋予了截然不同的激活特性。在表达Orai1的HEK293细胞中，43个氨基酸的STIM1 N末端与STIM2的嵌合替代减弱了Orai1介导的Ca2+进入，并大大减缓了储存诱导的Orai1通道激活。相反，在STIM1中取代的55个氨基酸的STIM2末端显著增强了Orai1介导的Ca2+进入和本构偶联，从而激活Orai1通道。因此，STIM N末端是强大的偶联修饰剂，在STIM2中发挥作用，“抑制”Orai1通道的本构激活，否则它对腔内Ca2+的高敏感性提供。
STIM1 and STIM2 are dynamic transmembrane endoplasmic reticulum Ca2+ sensors, coupling directly to activate plasma membrane Orai Ca2+ entry channels. Despite extensive sequence homology, the STIM proteins are functionally distinct. We reveal that the short variable N-terminal random coil sequences of STIM1 and STIM2 confer profoundly different activation properties. Using Orai1-expressing HEK293 cells, chimeric replacement of the 43-amino-acid STIM1 N terminus with that of STIM2 attenuates Orai1-mediated Ca2+ entry and drastically slows store-induced Orai1 channel activation. Conversely, the 55-amino-acid STIM2 terminus substituted within STIM1 strikingly enhances both Orai1-mediated Ca2+ entry and constitutive coupling to activate Orai1 channels. Hence, STIM N termini are powerful coupling modifiers, functioning in STIM2 to "brake" the otherwise constitutive activation of Orai1 channels afforded by its high sensitivity to luminal Ca2+.