Zhou Yandong, Mancarella Salvatore, Wang Youjun, Yue Chanyu, Ritchie Michael, Gill Donald L, Soboloff Jonathan
Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
J Biol Chem. 2009 Jul 17;284(29):19164-8. doi: 10.1074/jbc.C109.010900. Epub 2009 Jun 1.
STIM1 and STIM2 are dynamic transmembrane endoplasmic reticulum Ca(2+) sensors, coupling directly to activate plasma membrane Orai Ca(2+) 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 Ca(2+) entry and drastically slows store-induced Orai1 channel activation. Conversely, the 55-amino-acid STIM2 terminus substituted within STIM1 strikingly enhances both Orai1-mediated Ca(2+) 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 Ca(2+).
基质相互作用分子1（STIM1）和基质相互作用分子2（STIM2）是动态的跨膜内质网钙传感器，直接偶联以激活质膜上的Orai钙内流通道。尽管STIM蛋白具有广泛的序列同源性，但其功能却有所不同。我们发现，STIM1和STIM2的短可变N端无规卷曲序列赋予了截然不同的激活特性。在表达Orai1的人胚肾293（HEK293）细胞中，用STIM2的43个氨基酸的N端嵌合替换STIM1的N端，会减弱Orai1介导的钙内流，并显著减缓储存诱导的Orai1通道激活。相反，在STIM1中替换55个氨基酸的STIM2末端，会显著增强Orai1介导的钙内流以及激活Orai1通道的组成型偶联。因此，STIM的N端是强大的偶联调节剂，在STIM2中发挥作用，“制动”由其对内质网腔钙的高敏感性所导致的Orai1通道的组成型激活。
