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STIM1 的 CC3 区域中的 S417 对于 STIM1-Orai1 结合和 CRAC 通道激活至关重要。

S417 in the CC3 region of STIM1 is critical for STIM1-Orai1 binding and CRAC channel activation.

机构信息

Department of Clinical Laboratory, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Division of Histology and Embryology, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

出版信息

Life Sci Alliance. 2023 Jan 23;6(4). doi: 10.26508/lsa.202201623. Print 2023 Apr.

DOI:10.26508/lsa.202201623
PMID:36690443
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9873985/
Abstract

Store-operated Ca entry (SOCE) is a universal Ca influx pathway that is important for the function of many cell types. SOCE is controlled by the interaction of the ER Ca sensor STIM1 with the plasma membrane Ca channel Orai1. S417 is located in the third coiled-coil (CC3) domain of the C-terminus of STIM1. We found that single-point mutation of this residue (S417G) abolished STIM1 C-terminus interactions with Orai1. Mutation of S417 also abolished CAD-Orai1 binding and Orai1 channel activation, eliminated STIM1 puncta formation, and co-localization with Orai1 and SOCE. 2-APB was found to restore the binding of the STIM1 C-terminus mutant (S417G) to Orai1 and dose-dependently activate Orai1 channel. Both CBD and NBD of Orai1 are required for 2-APB-induced coupling between the Orai1 and STIM1 C-terminus mutant (S417G) and CRAC channel activation. We also demonstrated that 2-APB led to delayed activation of Orai1-K85E channel, although Orai1-K85E obviously impairs 2-APB-induced STIM1 C-terminus mutant (S417G)-Orai1 coupling. Our results suggest S417 in the CC3 domain of STIM1 is essential for STIM1-Orai1 binding and CRAC channel activation.

摘要

钙库操纵性钙内流（SOCE）是一种普遍存在的钙内流途径，对许多细胞类型的功能都很重要。SOCE 由内质网 Ca 传感器 STIM1 与质膜 Ca 通道 Orai1 的相互作用控制。S417 位于 STIM1 羧基末端的第三个卷曲螺旋（CC3）结构域。我们发现，该残基的单点突变（S417G）使 STIM1 羧基末端与 Orai1 的相互作用消失。S417 突变还消除了 CAD-Orai1 结合和 Orai1 通道的激活，消除了 STIM1 斑点的形成，以及与 Orai1 和 SOCE 的共定位。发现 2-APB 恢复了 STIM1 羧基末端突变体（S417G）与 Orai1 的结合，并剂量依赖性地激活 Orai1 通道。Orai1 的 CBD 和 NBD 都需要 2-APB 诱导 Orai1 和 STIM1 羧基末端突变体（S417G）之间的偶联，以及 CRAC 通道的激活。我们还证明，尽管 Orai1-K85E 明显损害 2-APB 诱导的 STIM1 羧基末端突变体（S417G）-Orai1 偶联，但 2-APB 导致 Orai1-K85E 通道的激活延迟。我们的结果表明，STIM1 中的 CC3 结构域中的 S417 对于 STIM1-Orai1 结合和 CRAC 通道的激活是必不可少的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8aa/9873985/d4c0406ea9db/LSA-2022-01623_Fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8aa/9873985/556b2e72bed3/LSA-2022-01623_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8aa/9873985/134410ea1512/LSA-2022-01623_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8aa/9873985/124cde9a37e5/LSA-2022-01623_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8aa/9873985/c715bfc48fce/LSA-2022-01623_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8aa/9873985/eaebc15a5461/LSA-2022-01623_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8aa/9873985/2afeda46a243/LSA-2022-01623_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8aa/9873985/bbd08bed1ecf/LSA-2022-01623_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8aa/9873985/840e5661a884/LSA-2022-01623_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8aa/9873985/0c0f7d94c981/LSA-2022-01623_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8aa/9873985/a1818b14eb7c/LSA-2022-01623_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8aa/9873985/2f5e1128669d/LSA-2022-01623_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8aa/9873985/d4c0406ea9db/LSA-2022-01623_Fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8aa/9873985/556b2e72bed3/LSA-2022-01623_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8aa/9873985/134410ea1512/LSA-2022-01623_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8aa/9873985/124cde9a37e5/LSA-2022-01623_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8aa/9873985/c715bfc48fce/LSA-2022-01623_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8aa/9873985/eaebc15a5461/LSA-2022-01623_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8aa/9873985/2afeda46a243/LSA-2022-01623_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8aa/9873985/bbd08bed1ecf/LSA-2022-01623_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8aa/9873985/840e5661a884/LSA-2022-01623_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8aa/9873985/0c0f7d94c981/LSA-2022-01623_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8aa/9873985/a1818b14eb7c/LSA-2022-01623_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8aa/9873985/2f5e1128669d/LSA-2022-01623_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8aa/9873985/d4c0406ea9db/LSA-2022-01623_Fig10.jpg

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