期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 19, 页码 6206-6211出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1418852112
关键词
STIM1; calcium; ORAI1; immunodeficiency; mutation
资金
- National Institutes of Health [NIH] [AI097302, NS057499]
- Canadian Institutes of Health Research
- Heart and Stroke Foundation of Canada
- Natural Sciences and Engineering Research Council of Canada
- Austrian Science Fund [FWF] [P25172, P27263]
- Bundesministerium fur Bildung und Forschung [BMBF Grant] [01EO1303]
- Deutsche Forschungsgemeinschaft Postdoctoral Fellowship [5303/1-1]
- Austrian Science Fund (FWF) [P 25172] Funding Source: researchfish
- Austrian Science Fund (FWF) [P27263, P25172] Funding Source: Austrian Science Fund (FWF)
Store-operated Ca2+ entry ( SOCE) is a universal Ca2+ influx pathway that is important for the function of many cell types. SOCE occurs upon depletion of endoplasmic reticulum (ER) Ca2+ stores and relies on a complex molecular interplay between the plasma membrane (PM) Ca2+ channel ORAI1 and the ER Ca2+ sensor stromal interaction molecule (STIM) 1. Patients with null mutations in ORAI1 or STIM1 genes present with severe combined immunodeficiency (SCID)-like disease. Here, we describe the molecular mechanisms by which a loss-of-function STIM1 mutation (R429C) in human patients abolishes SOCE. R429 is located in the third coiled-coil (CC3) domain of the cytoplasmic C terminus of STIM1. Mutation of R429 destabilizes the CC3 structure and alters the conformation of the STIM1 C terminus, thereby releasing a polybasic domain that promotes STIM1 recruitment to ER-PM junctions. However, the mutation also impairs cytoplasmic STIM1 oligomerization and abolishes STIM1-ORAI1 interactions. Thus, despite its constitutive localization at ER-PM junctions, mutant STIM1 fails to activate SOCE. Our results demonstrate multifunctional roles of the CC3 domain in regulating intra-and intermolecular STIM1 interactions that control (i) transition of STIM1 from a quiescent to an active conformational state, (ii) cytoplasmic STIM1 oligomerization, and (iii) STIM1-ORAI1 binding required for ORAI1 activation.
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