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

• DOI: 10.1073/pnas.1418852112
• Publication Date: 2015-04-30T21:24:52Z
• Authors: 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
• Keywords: 0301 basic medicine; Cytoplasm; Microscopy, Confocal; ORAI1 Protein; Homozygote; Immunologic Deficiency Syndromes; Mutation, Missense; Membrane Proteins; Genes, Recessive; Endoplasmic Reticulum; Neoplasm Proteins; Protein Structure, Tertiary; 03 medical and health sciences; HEK293 Cells; Fluorescence Resonance Energy Transfer; Humans; Calcium; Calcium Channels; Stromal Interaction Molecule 1; Dimerization

Significance

Stromal interaction molecule (STIM) 1 is an essential activator of the ORAI1 calcium (Ca 2+ ) channel that mediates Ca 2+ entry into many cell types. Patients with mutations in STIM1 or ORAI1 genes suffer from a severe immunodeficiency syndrome. Here, we studied a disease-causing mutant of STIM1 that is incapable of activating ORAI1 channels, thereby uncovering key molecular mechanisms of STIM1 function. The autosomal recessive R429C mutation interferes with the structural integrity of a protein–protein interaction domain in STIM1 and impairs the ability of STIM1 to multimerize and bind to ORAI1. Drugs targeting this domain may provide a means to selectively modulate STIM1–ORAI1 interaction and Ca 2+ entry as a novel approach to treat autoimmune diseases and other disorders associated with abnormal ORAI1-mediated Ca 2+ entry.