气候变化领域集成服务门户(CCPortal): The N terminus of Orai1 couples to the AKAP79 signaling complex to drive NFAT1 activation by local Ca2+entry

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DOI	10.1073/pnas.2012908118
	The N terminus of Orai1 couples to the AKAP79 signaling complex to drive NFAT1 activation by local Ca2+entry
	Kar P.; Lin Y.-P.; Bhardwaj R.; Tucker C.J.; Bird G.S.; Hediger M.A.; Monico C.; Amin N.; Parekh A.B.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:19
英文摘要	To avoid conflicting and deleterious outcomes, eukaryotic cells often confine second messengers to spatially restricted subcompartments. The smallest signaling unit is the Ca2+nanodomain, which forms when Ca2+channels open. Ca2+nanodomains arising from store-operated Orai1 Ca2+channels stimulate the protein phosphatase calcineurin to activate the transcription factor nuclear factor of activated T cells (NFAT). Here,we show that NFAT1 tethered directly to the scaffolding protein AKAP79 (A-kinase anchoring protein 79) is activated by local Ca2+entry, providing a mechanism to selectively recruit a transcription factor. We identify the region on the N terminus of Orai1 that interacts with AKAP79 and demonstrate that this site is essential for physiological excitation-transcription coupling. NMR structural analysis of the AKAP binding domain reveals a compact shape with several proline-driven turns. Orai2 and Orai3, isoforms of Orai1, lack this region and therefore are less able to engage AKAP79 and activate NFAT. A shorter, naturally occurring Orai1 protein that arises from alternative translation initiation also lacks the AKAP79-interaction site and fails to activate NFAT1. Interfering with Orai1-AKAP79 interaction suppresses cytokine production, leaving other Ca2+channel functions intact. Our results reveal the mechanistic basis for how a subtype of a widely expressed Ca2+channel is able to activate a vital transcription pathway and identify an approach for generation of immunosuppressant drugs. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	AKAP79; Calcium channel; Store-operated; Transcription factor
语种	英语
scopus关键词	A kinase anchoring protein 79; calcium ion; calcium release activated calcium channel; calcium release activated calcium channel 1; calcium release activated calcium channel 2; calcium release activated calcium channel 3; interleukin 5; proline; scaffold protein; transcription factor; transcription factor NFAT1; unclassified drug; AKAP5 protein, human; calcineurin; calcium; calcium channel; calcium release activated calcium channel 1; cyclic AMP dependent protein kinase anchoring protein; cytokine; NFATC2 protein, human; ORAI1 protein, human; transcription factor; transcription factor NFAT; transcriptome; amino terminal sequence; Article; binding site; breast cancer; calcium transport; controlled study; cytokine production; embryo; exocytosis; HEK293 cell line; human; human cell; MCF-7 cell line; protein expression; protein protein interaction; translation initiation; calcium signaling; chemistry; gene expression regulation; gene knockout; genetics; metabolism; physiology; signal transduction; A Kinase Anchor Proteins; Calcineurin; Calcium; Calcium Channels; Calcium Signaling; Cytokines; Gene Expression Regulation; Gene Knockout Techniques; HEK293 Cells; Humans; MCF-7 Cells; NFATC Transcription Factors; ORAI1 Protein; Signal Transduction; Transcription Factors; Transcriptome
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251191
作者单位	Department of Physiology, Anatomy and Genetics, Oxford University, Oxford, OX1 3PT, United Kingdom; Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, United States; Department of Nephrology and Hypertension, University Hospital Bern, Inselspital, Bern, 3010, Switzerland; Micron Oxford Advanced Bioimaging Unit, Department of Biochemistry, Oxford University, Oxford, OX1 3QU, United Kingdom; Department of Chemistry, Oxford University, Oxford, OX1 3TA, United Kingdom
推荐引用方式 GB/T 7714	Kar P.,Lin Y.-P.,Bhardwaj R.,et al. The N terminus of Orai1 couples to the AKAP79 signaling complex to drive NFAT1 activation by local Ca2+entry[J],2021,118(19).
APA	Kar P..,Lin Y.-P..,Bhardwaj R..,Tucker C.J..,Bird G.S..,...&Parekh A.B..(2021).The N terminus of Orai1 couples to the AKAP79 signaling complex to drive NFAT1 activation by local Ca2+entry.Proceedings of the National Academy of Sciences of the United States of America,118(19).
MLA	Kar P.,et al."The N terminus of Orai1 couples to the AKAP79 signaling complex to drive NFAT1 activation by local Ca2+entry".Proceedings of the National Academy of Sciences of the United States of America 118.19(2021).