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Transmembrane helix connectivity in Orai1 controls two gates for calcium-dependent transcription

Item Type:Article
Title:Transmembrane helix connectivity in Orai1 controls two gates for calcium-dependent transcription
Creators Name:Frischauf, I. and Litvinukova, M. and Schober, R. and Zayats, V. and Svobodova, B. and Bonhenry, D. and Lunz, V. and Cappello, S. and Tociu, L. and Reha, D. and Stallinger, A. and Hochreiter, A. and Pammer, T. and Butorac, C. and Muik, M. and Groschner, K. and Bogeski, I. and Ettrich, R.H. and Romanin, C. and Schindl, R.
Abstract:The channel Orai1 requires Ca(2+) store depletion in the endoplasmic reticulum and an interaction with the Ca(2+) sensor STIM1 to mediate Ca(2+) signaling. Alterations in Orai1-mediated Ca(2+) influx have been linked to several pathological conditions including immunodeficiency, tubular myopathy, and cancer. We screened large-scale cancer genomics data sets for dysfunctional Orai1 mutants. Five of the identified Orai1 mutations resulted in constitutively active gating and transcriptional activation. Our analysis showed that certain Orai1 mutations were clustered in the transmembrane 2 helix surrounding the pore, which is a trigger site for Orai1 channel gating. Analysis of the constitutively open Orai1 mutant channels revealed two fundamental gates that enabled Ca(2+) influx: Arginine side chains were displaced so they no longer blocked the pore, and a chain of water molecules formed in the hydrophobic pore region. Together, these results enabled us to identify a cluster of Orai1 mutations that trigger Ca2+ permeation associated with gene transcription and provide a gating mechanism for Orai1.
Keywords:Arginine, Calcium, Cell Membrane, Genomics, HCT116 Cells, HEK293 Cells, Ion Channel Gating, Molecular Dynamics Simulation, Muscular Diseases, Mutation, Neoplasm Proteins, Neoplasms, ORAI1 Protein, Patch-Clamp Techniques, Protein Structure, Secondary, Stromal Interaction Molecule 1, Transcriptional Activation, Animals, Drosophila melanogaster
Source:Science Signaling
ISSN:1945-0877
Publisher:American Association for the Advancement of Science (U.S.A.)
Volume:10
Number:507
Page Range:eaao0358
Date:28 November 2017
Official Publication:https://doi.org/10.1126/scisignal.aao0358
PubMed:View item in PubMed

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