title: Inside-out Ca(2+) signalling prompted by STIM1 conformational switch.
abstract: Store-operated Ca(2+) entry mediated by STIM1 and ORAI1 constitutes one of the major Ca(2+) entry routes in mammalian cells. The molecular choreography of STIM1-ORAI1 coupling is initiated by endoplasmic reticulum (ER) Ca(2+) store depletion with subsequent oligomerization of the STIM1 ER-luminal domain, followed by its redistribution towards the plasma membrane to gate ORAI1 channels. The mechanistic underpinnings of this inside-out Ca(2+) signalling were largely undefined. By taking advantage of a unique gain-of-function mutation within the STIM1 transmembrane domain (STIM1-TM), here we show that local rearrangement, rather than alteration in the oligomeric state of STIM1-TM, prompts conformational changes in the cytosolic juxtamembrane coiled-coil region. Importantly, we further identify critical residues within the cytoplasmic domain of STIM1 (STIM1-CT) that entail autoinhibition. On the basis of these findings, we propose a model in which STIM1-TM reorganization switches STIM1-CT into an extended conformation, thereby projecting the ORAI-activating domain to gate ORAI1 channels.
authors.affiliation: Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030, USA.
authors.forename: Guolin
authors.initials: G
authors.lastname: Ma
authors.affiliation: Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Wei
authors.affiliation: Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030, USA.
authors.forename: Lian
authors.initials: L
authors.lastname: He
authors.affiliation: High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China.|University of Science and Technology of China, Hefei, Anhui 230036, China.
authors.forename: Chongxu
authors.initials: C
authors.lastname: Liu
authors.affiliation: High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wu
authors.affiliation: Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, Texas 76504, USA.
authors.forename: Shenyuan L
authors.initials: SL
authors.lastname: Zhang
authors.affiliation: Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030, USA.
authors.forename: Ji
authors.initials: J
authors.lastname: Jing
authors.affiliation: Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030, USA.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of Biochemistry, University of Wisconsin Madison, Madison, Wisconsin 53706, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Senes
authors.affiliation: Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Tan
authors.affiliation: College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Siwei
authors.initials: S
authors.lastname: Li
authors.affiliation: Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
authors.forename: Aomin
authors.initials: A
authors.lastname: Sun
authors.affiliation: High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China.
authors.forename: Yunchen
authors.initials: Y
authors.lastname: Bi
authors.affiliation: Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhong
authors.affiliation: Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, Texas 76504, USA.
authors.forename: Hongjiang
authors.initials: H
authors.lastname: Si
authors.affiliation: College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Yuequan
authors.identifier: http://orcid.org/0000-0002-3775-0900
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Key Laboratory of Chemical Biology, School of Pharmacy, Shandong University, Jinan, Shandong 250012, China.
authors.forename: Minyong
authors.identifier: http://orcid.org/0000-0003-3276-4921
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Mi-Sun
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Weibin
authors.initials: W
authors.lastname: Zhou
authors.affiliation: High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China.|University of Science and Technology of China, Hefei, Anhui 230036, China.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Wang
authors.affiliation: Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
authors.forename: Youjun
authors.identifier: http://orcid.org/0000-0003-0961-1716
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030, USA.|Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, Texas 76504, USA.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling; D002853:Chromatography, Liquid; D002942:Circular Dichroism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004926:Escherichia coli; D049452:Green Fluorescent Proteins; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008164:Luminescent Proteins; D008565:Membrane Proteins / Q000378:metabolism*; D018613:Microscopy, Confocal; D008958:Models, Molecular; D063347:Native Polyacrylamide Gel Electrophoresis; D009363:Neoplasm Proteins / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D000071740:ORAI1 Protein; D018408:Patch-Clamp Techniques; D011487:Protein Conformation; D011994:Recombinant Proteins; D013050:Spectrometry, Fluorescence; D000071737:Stromal Interaction Molecule 1; D020349:Surface Plasmon Resonance; D000097573:Red Fluorescent Protein
chemical_list: D015220:Calcium Channels; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; D011994:Recombinant Proteins; D000071737:Stromal Interaction Molecule 1; D000097573:Red Fluorescent Protein; C510746:ORAI1 protein, human; C103530:STIM1 protein, human