Missense mutation in immunodeficient patients shows the multifunctional roles of coiled-coil domain 3 (CC3) in STIM1 activation

Mate Maus, Amit Jairaman, Peter B. Stathopulos, Martin Muik, Marc Fahrner, Carl Weidinger, Melina Benson, Sebastian Fuchs, Stephan Ehl, Christoph Romanin, Mitsuhiko Ikura, Murali Prakriya, Stefan Feske*

*Corresponding author for this work

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6206-6211
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number19
DOIs
StatePublished - May 12 2015

Keywords

  • Calcium
  • Immunodeficiency
  • Mutation
  • ORAI1
  • STIM1

ASJC Scopus subject areas

  • General

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    Maus, M., Jairaman, A., Stathopulos, P. B., Muik, M., Fahrner, M., Weidinger, C., Benson, M., Fuchs, S., Ehl, S., Romanin, C., Ikura, M., Prakriya, M., & Feske, S. (2015). Missense mutation in immunodeficient patients shows the multifunctional roles of coiled-coil domain 3 (CC3) in STIM1 activation. Proceedings of the National Academy of Sciences of the United States of America, 112(19), 6206-6211. https://doi.org/10.1073/pnas.1418852112