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在储存耗竭期间，PI(4,5)P2含量低和PI(4,5)P2含量高的微结构域之间的易位决定了STIM1的构象和Orai1的门控。

Translocation between PI(4,5)P2-poor and PI(4,5)P2-rich microdomains during store depletion determines STIM1 conformation and Orai1 gating.

作者信息

Maléth Jozsef, Choi Seok, Muallem Shmuel, Ahuja Malini

机构信息

1] Epithelial Signaling and Transport Section, Molecular Physiology and Therapeutics Branch, NIDCR, NIH, Bethesda, Maryland 20892, USA [2] First Department of Medicine, University of Szeged, H-6725 Szeged, Hungary.

1] Epithelial Signaling and Transport Section, Molecular Physiology and Therapeutics Branch, NIDCR, NIH, Bethesda, Maryland 20892, USA [2] Department of Physiology, College of Medicine, Chosun University, Chosun 501-375, South Korea.

出版信息

Nat Commun. 2014 Dec 17;5:5843. doi: 10.1038/ncomms6843.

DOI:10.1038/ncomms6843
PMID:25517631
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4270102/
Abstract

The Orai1-STIM1 current undergoes slow Ca(2+)-dependent inactivation (SCDI) mediated by the binding of SARAF to STIM1. Here we report the use of SCDI by SARAF as a probe of the conformation and microdomain localization of the Orai1-STIM1 complex. We find that the interaction of STIM1 with Orai1 carboxyl terminus (C terminus) and the STIM1 K-domain are required for the interaction of SARAF with STIM1 and SCDI. STIM1-Orai1 must be in a PM/ER microdomain tethered by E-Syt1, stabilized by septin4 and enriched in PI(4,5)P2 for STIM1-SARAF interaction. Targeting STIM1 to PI(4,5)P2-rich and -poor microdomains reveals that SARAF-dependent SCDI is observed only when STIM1-Orai1 are within the PI(4,5)P2-rich microdomain. Notably, store depletion results in transient localization of STIM1-Orai1 in the PI(4,5)P2-poor microdomain, which then translocates to the PI(4,5)P2-rich domain. These findings reveal the role of PM/ER tethers in the regulation of Orai1 function and a mode of regulation by PI(4,5)P2 involving translocation between PI(4,5)P2 microdomains.

摘要

Orai1-STIM1电流会经历由SARAF与STIM1结合介导的缓慢的Ca(2+)依赖性失活（SCDI）。在此，我们报告利用SARAF的SCDI作为Orai1-STIM1复合物构象和微区定位的探针。我们发现，SARAF与STIM1的相互作用以及SCDI需要STIM1与Orai1羧基末端（C末端）和STIM1 K结构域相互作用。对于STIM1-SARAF相互作用，STIM1-Orai1必须处于由E-Syt1系留、由septin4稳定并富含PI(4,5)P2的质膜/内质网微区中。将STIM1靶向富含和缺乏PI(4,5)P2的微区表明，只有当STIM1-Orai1处于富含PI(4,5)P2的微区时才会观察到SARAF依赖性SCDI。值得注意的是，储存耗尽导致STIM1-Orai1在缺乏PI(4,5)P2的微区短暂定位，随后转移到富含PI(4,5)P2的区域。这些发现揭示了质膜/内质网系留在Orai1功能调节中的作用以及PI(4,5)P2通过在PI(4,5)P2微区之间转位进行调节的模式。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d158/4270102/6011fb03bddb/nihms-642455-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d158/4270102/a6e2d13d8466/nihms-642455-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d158/4270102/0c7bbf9be7d7/nihms-642455-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d158/4270102/60caa01ebe71/nihms-642455-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d158/4270102/d9679a2a48e0/nihms-642455-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d158/4270102/030241421951/nihms-642455-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d158/4270102/15b93edaf027/nihms-642455-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d158/4270102/6011fb03bddb/nihms-642455-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d158/4270102/a6e2d13d8466/nihms-642455-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d158/4270102/0c7bbf9be7d7/nihms-642455-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d158/4270102/60caa01ebe71/nihms-642455-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d158/4270102/d9679a2a48e0/nihms-642455-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d158/4270102/030241421951/nihms-642455-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d158/4270102/15b93edaf027/nihms-642455-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d158/4270102/6011fb03bddb/nihms-642455-f0007.jpg

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