Journal Article

A dual mechanism promotes switching of the Stormorken STIM1 R304W mutant into the activated state

Müller, Norbert, Ikura, Mitsu, Muik, Martin, Stathopulos, Peter, Romanin, Christoph, Fahrner, Marc, Stadlbauer, Michael, Rathner, Petr

2018

Overview

STIM1 and Orai1 are key components of the Ca 2+ -release activated Ca 2+ (CRAC) current. Orai1, which represents the subunit forming the CRAC channel complex, is activated by the ER resident Ca 2+ sensor STIM1. The genetically inherited Stormorken syndrome disease has been associated with the STIM1 single point R304W mutant. The resulting constitutive activation of Orai1 mainly involves the CRAC-activating domain CAD/SOAR of STIM1, the exposure of which is regulated by the molecular interplay between three cytosolic STIM1 coiled-coil (CC) domains. Here we present a dual mechanism by which STIM1 R304W attains the pathophysiological, constitutive activity eliciting the Stormorken syndrome. The R304W mutation induces a helical elongation within the CC1 domain, which together with an increased CC1 homomerization, destabilize the resting state of STIM1. This culminates, even in the absence of store depletion, in structural extension and CAD/SOAR exposure of STIM1 R304W leading to constitutive CRAC channel activation and Stormorken disease. Stormorken syndrome is associated with the R304W mutation in STIM1, which is a Calcium sensor in the endoplasmic reticulum. Here authors use FRET and electrophysiology to show that R304W induces STIM1 conformational extension by a dual mechanism resulting in constitutive activation of Ca2+ channels.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/6 / 13/109 / 14/19 / 14/33 / 631/80/86/1999 / 692/699 / 82/29 / 82/83 / 9/74 / Activation / Amino Acid Sequence / Amino Acid Substitution / Bacterial Proteins - genetics / Bacterial Proteins - metabolism / Binding Sites / Biophysics / Blood Platelet Disorders - genetics / Blood Platelet Disorders - metabolism / Blood Platelet Disorders - pathology / Calcium - chemistry / Calcium - metabolism / Calcium channels / Calcium ions / Dyslexia - genetics / Dyslexia - metabolism / Dyslexia - pathology / Elongation / Erythrocytes, Abnormal - metabolism / Erythrocytes, Abnormal - pathology / Experiments / Gene Expression / Gene Expression Regulation / Genes, Reporter / Green Fluorescent Proteins - genetics / Green Fluorescent Proteins - metabolism / HEK293 Cells / Humanities and Social Sciences / Humans / Ichthyosis - genetics / Ichthyosis - metabolism / Ichthyosis - pathology / Ion Transport / Localization / Luminescent Proteins - genetics / Luminescent Proteins - metabolism / Migraine Disorders - genetics / Migraine Disorders - metabolism / Migraine Disorders - pathology / Miosis - genetics / Miosis - metabolism / Miosis - pathology / Models, Molecular / multidisciplinary / Muscle Fatigue - genetics / Mutation / Neoplasm Proteins - chemistry / Neoplasm Proteins - genetics / Neoplasm Proteins - metabolism / NMR / Nuclear magnetic resonance / Orai1 protein / ORAI1 Protein - chemistry / ORAI1 Protein - genetics / ORAI1 Protein - metabolism / Patch-Clamp Techniques / Physiology / Point Mutation / Protein Binding / Protein Conformation, alpha-Helical / Protein Interaction Domains and Motifs / Protein Multimerization / Recombinant Proteins - chemistry / Recombinant Proteins - genetics / Recombinant Proteins - metabolism / Science / Science (multidisciplinary) / Spleen - abnormalities / Spleen - metabolism / Spleen - pathology / STIM1 protein / Stromal Interaction Molecule 1 - chemistry / Stromal Interaction Molecule 1 - genetics / Stromal Interaction Molecule 1 - metabolism