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Ion and pH Sensitivity of a TMBIM Ca2+ Channel.

Structure. 2019 Jun 04;27(6):1013-1021.e3. Epub 2019 Mar 28
Gongrui Guo 1 , Min Xu 2 , Yanqi Chang 3 , Tomas Luyten 4 , Bruno Seitaj 4 , Wu Liu 1 , Ping Zhu 5 , Geert Bultynck 4 , Lei Shi 6 , Matthias Quick 7 , Qun Liu 8
Gongrui Guo 1 , Min Xu 2 , Yanqi Chang 3 , Tomas Luyten 4 , Bruno Seitaj 4 , Wu Liu 1 , Ping Zhu 5 , Geert Bultynck 4 , Lei Shi 6 , Matthias Quick 7 , Qun Liu 8
+ et al

[No authors listed]

Author information
  • 1 Biology Department, Brookhaven National Laboratory, Upton, NY 11973, USA; NSLS-II, Brookhaven National Laboratory, Upton, NY 11973, USA.
  • 2 Computational Chemistry and Molecular Biophysics Unit, National Institute on Drug Abuse - Intramural Research Program, National Institutes of Health, Baltimore, MA 21224, USA.
  • 3 New York Consortium on Membrane Protein Structure, New York Structural Biology Center, New York, NY 10027, USA.
  • 4 Laboratory Molecular and Cellular Signaling, Department Cellular and Molecular Medicine, Campus Gasthuisberg O/N-I Bus 802, Herestraat 49 3000 Leuven, Belgium.
  • 5 Biology Department, Brookhaven National Laboratory, Upton, NY 11973, USA.
  • 6 Computational Chemistry and Molecular Biophysics Unit, National Institute on Drug Abuse - Intramural Research Program, National Institutes of Health, Baltimore, MA 21224, USA. Electronic address: lei.shi2@nih.gov.
  • 7 Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY 10032, USA. Electronic address: mq2102@cumc.columbia.edu.
  • 8 Biology Department, Brookhaven National Laboratory, Upton, NY 11973, USA; NSLS-II, Brookhaven National Laboratory, Upton, NY 11973, USA. Electronic address: qunliu@bnl.gov.

摘要

The anti-apoptotic transmembrane Bax inhibitor motif (TMBIM) containing protein family regulates Ca2+ homeostasis, cell death, and the progression of diseases including cancers. The recent crystal structures of the TMBIM homolog BsYetJ reveal a conserved Asp171-Asp195 dyad that is proposed in regulating a pH-dependent Ca2+ translocation. Here we show that BsYetJ mediates Ca2+ fluxes in permeabilized mammalian cells, and its interaction with Ca2+ is sensitive to protons and other cations. We report crystal structures of BsYetJ in additional states, revealing the flexibility of the dyad in a closed state and a pore-opening mechanism. Functional studies show that the dyad is responsible for both Ca2+ affinity and pH dependence. Computational simulations suggest that protonation of Asp171 weakens its interaction with Arg60, leading to an open state. Our integrated analysis provides insights into the regulation of the BsYetJ Ca2+ channel that may inform understanding of human TMBIM proteins regarding their roles in cell death and diseases. Copyright © 2019 Elsevier Ltd. All rights reserved.

KEYWORDS: Ca(2+) channel structure, Ca(2+) efflux, ion sensitivity, molecular dynamics simulation, pH sensor, proton sensitivity

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