Stormorken syndrome is a multiorgan hereditary disease caused by dysfunction of the endoplasmic reticulum (ER) Ca2+ sensor protein STIM1, which forms the Ca2+ release-activated Ca2+ (CRAC) channel together with the plasma membrane channel Orai1. ER Ca2+ store depletion activates STIM1 by releasing the intramolecular "clamp" formed between the coiled coil 1 (CC1) and CC3 domains of the protein, enabling the C terminus to extend and interact with Orai1. The most frequently occurring mutation in patients with Stormorken syndrome is R304W, which destabilizes and extends the STIM1 C terminus independently of ER Ca2+ store depletion, causing constitutive binding to Orai1 and CRAC channel activation. We found that in cis deletion of one amino acid residue, Glu296 (which we called E296del) reversed the pathological effects of R304W. Homozygous Stim1 E296del+R304W mice were viable and phenotypically indistinguishable from wild-type mice. NMR spectroscopy, molecular dynamics simulations, and cellular experiments revealed that although the R304W mutation prevented CC1 from interacting with CC3, the additional deletion of Glu296 opposed this effect by enabling CC1-CC3 binding and restoring the CC domain interactions within STIM1 that are critical for proper CRAC channel function. Our results provide insight into the activation mechanism of STIM1 by clarifying the molecular basis of mutation-elicited protein dysfunction and pathophysiology.

• MeSH
• abnormální erytrocyty MeSH
• aminokyseliny metabolismus   MeSH
• dyslexie MeSH
• endoplazmatické retikulum metabolismus   MeSH
• ichtyóza MeSH
• kanály aktivované uvolněním vápníku * genetika   MeSH
• membránové proteiny * metabolismus   MeSH
• migréna MeSH
• mióza MeSH
• mutace MeSH
• myši MeSH
• protein ORAI1 metabolismus   MeSH
• protein STIM1 genetika   MeSH
• slezina abnormality   MeSH
• svalová únava MeSH
• trombocytopatie MeSH
• vápník metabolismus   MeSH
• vápníkové kanály metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aminokyseliny MeSH
• kanály aktivované uvolněním vápníku * MeSH
• membránové proteiny * MeSH
• protein ORAI1 MeSH
• protein STIM1 MeSH
• Stim1 protein, mouse MeSH Prohlížeč
• vápník MeSH
• vápníkové kanály MeSH