Research ArticleCalcium signaling

Sequential activation of STIM1 links Ca2+ with luminal domain unfolding

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Science Signaling  19 Nov 2019:
Vol. 12, Issue 608, eaax3194
DOI: 10.1126/scisignal.aax3194

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Keeping STIM1 unSTIMulated

Upon ER Ca2+ depletion, the ER-localized Ca2+ sensor STIM1 activates the Orai family of plasma membrane–localized Ca2+ channels to replenish Ca2+ stores. Schober et al. described the conformational changes that occur during the initial steps of STIM1 activation. The authors used biochemical and electrophysiological analyses and molecular dynamics simulations to characterize constitutively active STIM1 mutants associated with tubular aggregate myopathy or cancer, as well as naturally occurring STIM1 variants. Their results indicated that although STIM1 was stabilized by the binding of a single Ca2+ ion, it could bind to multiple Ca2+ ions, a property that was disrupted by disease-associated mutations. Furthermore, these mutations caused STIM1 to adopt an unfolded conformation similar to that caused by Ca2+ depletion in wild-type STIM1.

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