TY - JOUR
T1 - Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation
AU - Luik, Riina M.
AU - Wang, Bin
AU - Prakriya, Murali
AU - Wu, Minnie M.
AU - Lewis, Richard S.
PY - 2008/7/24
Y1 - 2008/7/24
N2 - Ca2+-release-activated Ca2+ (CRAC) channels generate sustained Ca2+ signals that are essential for a range of cell functions, including antigen-stimulated T lymphocyte activation and proliferation. Recent studies have revealed that the depletion of Ca 2+ from the endoplasmic reticulum (ER) triggers the oligomerization of stromal interaction molecule 1 (STIM1), the ER Ca2+ sensor, and its redistribution to ER-plasma membrane (ER-PM) junctions where the CRAC channel subunit ORAI1 accumulates in the plasma membrane and CRAC channels open. However, how the loss of ER Ca2+ sets into motion these coordinated molecular rearrangements remains unclear. Here we define the relationships among [Ca2+]ER, STIM1 redistribution and CRAC channel activation and identify STIM1 oligomerization as the critical [Ca 2+]ER-dependent event that drives store-operated Ca 2+ entry. In human Jurkat leukaemic T cells expressing an ER-targeted Ca2+ indicator, CRAC channel activation and STIM1 redistribution follow the same function of [Ca2+]ER, reaching half-maximum at ∼200 μM with a Hill coefficient of ∼4. Because STIM1 binds only a single Ca2+ ion, the high apparent cooperativity suggests that STIM1 must first oligomerize to enable its accumulation at ER-PM junctions. To assess directly the causal role of STIM1 oligomerization in store-operated Ca2+ entry, we replaced the luminal Ca 2+-sensing domain of STIM1 with the 12-kDa FK506- and rapamycin-binding protein (FKBP12, also known as FKBP1A) or the FKBP-rapamycin binding (FRB) domain of the mammalian target of rapamycin (mTOR, also known as FRAP1). A rapamycin analogue oligomerizes the fusion proteins and causes them to accumulate at ER-PM junctions and activate CRAC channels without depleting Ca2+ from the ER. Thus, STIM1 oligomerization is the critical transduction event through which Ca2+ store depletion controls store-operated Ca2+ entry, acting as a switch that triggers the self-organization and activation of STIM1-ORAI1 clusters at ER-PM junctions.
AB - Ca2+-release-activated Ca2+ (CRAC) channels generate sustained Ca2+ signals that are essential for a range of cell functions, including antigen-stimulated T lymphocyte activation and proliferation. Recent studies have revealed that the depletion of Ca 2+ from the endoplasmic reticulum (ER) triggers the oligomerization of stromal interaction molecule 1 (STIM1), the ER Ca2+ sensor, and its redistribution to ER-plasma membrane (ER-PM) junctions where the CRAC channel subunit ORAI1 accumulates in the plasma membrane and CRAC channels open. However, how the loss of ER Ca2+ sets into motion these coordinated molecular rearrangements remains unclear. Here we define the relationships among [Ca2+]ER, STIM1 redistribution and CRAC channel activation and identify STIM1 oligomerization as the critical [Ca 2+]ER-dependent event that drives store-operated Ca 2+ entry. In human Jurkat leukaemic T cells expressing an ER-targeted Ca2+ indicator, CRAC channel activation and STIM1 redistribution follow the same function of [Ca2+]ER, reaching half-maximum at ∼200 μM with a Hill coefficient of ∼4. Because STIM1 binds only a single Ca2+ ion, the high apparent cooperativity suggests that STIM1 must first oligomerize to enable its accumulation at ER-PM junctions. To assess directly the causal role of STIM1 oligomerization in store-operated Ca2+ entry, we replaced the luminal Ca 2+-sensing domain of STIM1 with the 12-kDa FK506- and rapamycin-binding protein (FKBP12, also known as FKBP1A) or the FKBP-rapamycin binding (FRB) domain of the mammalian target of rapamycin (mTOR, also known as FRAP1). A rapamycin analogue oligomerizes the fusion proteins and causes them to accumulate at ER-PM junctions and activate CRAC channels without depleting Ca2+ from the ER. Thus, STIM1 oligomerization is the critical transduction event through which Ca2+ store depletion controls store-operated Ca2+ entry, acting as a switch that triggers the self-organization and activation of STIM1-ORAI1 clusters at ER-PM junctions.
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U2 - 10.1038/nature07065
DO - 10.1038/nature07065
M3 - Article
C2 - 18596693
AN - SCOPUS:47949132511
VL - 454
SP - 538
EP - 542
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7203
ER -