Ion and pH Sensitivity of a TMBIM Ca2+ Channel

Gongrui Guo; Min Xu; Yanqi Chang; Tomas Luyten; Bruno Seitaj; Wu Liu; Ping Zhu; Geert Bultynck; Lei Shi; Matthias Quick; Qun Liu

doi:10.1016/j.str.2019.03.003

Ion and pH Sensitivity of a TMBIM Ca²⁺ Channel

Structure. 2019 Jun 4;27(6):1013-1021.e3. doi: 10.1016/j.str.2019.03.003. Epub 2019 Mar 28.

Authors

Gongrui Guo¹, Min Xu², Yanqi Chang³, Tomas Luyten⁴, Bruno Seitaj⁴, Wu Liu¹, Ping Zhu⁵, Geert Bultynck⁴, Lei Shi⁶, Matthias Quick⁷, Qun Liu⁸

Affiliations

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.

Abstract

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.

Keywords: Ca(2+) channel structure; Ca(2+) efflux; ion sensitivity; molecular dynamics simulation; pH sensor; proton sensitivity.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Amino Acid Motifs
Apoptosis
Bacillus subtilis / genetics
Bacillus subtilis / metabolism
Bacterial Proteins / chemistry
Bacterial Proteins / genetics
Bacterial Proteins / metabolism
Calcium / metabolism*
Crystallography, X-Ray
HeLa Cells
Humans
Hydrogen-Ion Concentration
Membrane Proteins / chemistry
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Molecular Dynamics Simulation
Protein Binding
Protons*

Substances

Bacterial Proteins
Membrane Proteins
Protons
RECS1 protein, mouse
Calcium

Abstract

Publication types

MeSH terms

Substances

Grants and funding