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Ion and pH Sensitivity of a TMBIM Ca2+ Channel

Gongrui Guo1, Min Xu2, Yanqi Chang3

  • 1Biology Department, Brookhaven National Laboratory, Upton, NY 11973, USA; NSLS-II, Brookhaven National Laboratory, Upton, NY 11973, USA.

Structure (London, England : 1993)
|April 2, 2019
PubMed

Insights

The transmembrane Bax inhibitor motif (TMBIM) protein family regulates calcium (Ca2+) homeostasis and cell death. This study reveals how a specific TMBIM protein, BsYetJ, controls Ca2+ flow and pH sensitivity, offering insights into disease-related functions.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • The transmembrane Bax inhibitor motif (TMBIM) protein family is crucial for regulating calcium (Ca2+) homeostasis, cell death, and disease progression, including cancer.
  • A conserved Asp171-Asp195 dyad in the TMBIM homolog BsYetJ is hypothesized to control pH-dependent Ca2+ translocation.

Purpose of the Study:

  • To elucidate the structural and functional mechanisms underlying Ca2+ translocation mediated by BsYetJ.
  • To investigate the role of the Asp171-Asp195 dyad in Ca2+ binding and pH sensitivity.
  • To provide insights into the regulation of human TMBIM proteins.

Main Methods:

  • Functional characterization of BsYetJ-mediated Ca2+ fluxes in permeabilized mammalian cells.
  • Determination of crystal structures of BsYetJ in multiple states.
  • Computational simulations to model protonation effects on the dyad and channel gating.

Main Results:

  • BsYetJ mediates Ca2+ fluxes sensitive to protons and other cations.
  • New crystal structures reveal dyad flexibility and a pore-opening mechanism.
  • The Asp171-Asp195 dyad is essential for both Ca2+ affinity and pH dependence.
  • Computational simulations indicate protonation of Asp171 triggers channel opening by disrupting interactions.

Conclusions:

  • The study elucidates the regulatory mechanism of the BsYetJ Ca2+ channel, highlighting the critical role of the Asp171-Asp195 dyad in gating and ion selectivity.
  • Findings offer a mechanistic understanding of pH-dependent ion transport in TMBIM proteins.
  • This research provides a foundation for understanding the involvement of human TMBIMs in cell death and disease.
Keywords:
Ca(2+) channel structureCa(2+) effluxion sensitivitymolecular dynamics simulationpH sensorproton sensitivity

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