Activation of STIM1-Orai1 Involves an Intramolecular Switching Mechanism

被引：173

作者：

Korzeniowski, Marek K. ^{[1
]}

Martin Manjarres, Isabel ^{[2
]}

Varnai, Peter ^{[3
]}

Balla, Tamas ^{[1
]}

机构：

[1] NICHHD, Sect Mol Signal Transduct, Program Dev Neurosci, Bethesda, MD 20892 USA

[2] Univ Valladolid, CSIC, Inst Biol & Genet Mol, Valladolid 47003, Spain

[3] Semmelweis Univ, Fac Med, Dept Physiol, H-1094 Budapest, Hungary

来源：

SCIENCE SIGNALING | 2010年 / 3卷 / 148期

基金：

英国医学研究理事会; 匈牙利科学研究基金会;

关键词：

OPERATED CALCIUM-ENTRY; CRAC CHANNEL; ORAI CHANNELS; CA2+-DEPENDENT INACTIVATION; MOLECULAR DETERMINANTS; ENDOPLASMIC-RETICULUM; COILED-COIL; STIM1; GATES; CA2+ INFLUX; DEPLETION;

D O I：

10.1126/scisignal.2001122

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Stromal interaction molecule 1 (STIM1) stimulates calcium ion (Ca2+) entry through plasma membrane Orai1 channels in response to decreased Ca2+ concentrations in the endoplasmic reticulum lumen. We identified an acidic motif within the STIM1 coiled-coil region that keeps its Ca2+ activation domain [Ca2+ release-activated Ca2+ (CRAC) activation domain/STIM1-Orai activating region (CAD/SOAR)]-a cytoplasmic region required for its activation of Orai1-inactive. The sequence of the STIM1 acidic motif shows substantial similarity to that of the carboxyl-terminal coiled-coil segment of Orai1, which is the postulated site of interaction with STIM1. Mutations within this acidic region rendered STIM1 constitutively active, whereas mutations within a short basic segment of CAD/SOAR prevented Orai1 activation. We propose that the CAD/SOAR domain is released from an intramolecular clamp during STIM1 activation, allowing the basic segment to activate Orai1 channels. This evolutionarily conserved mechanism of STIM1 activation resembles the regulation of protein kinases by intramolecular silencing through pseudosubstrate binding.

引用

页数：9

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