What is it about?

The endoplasmic reticulum (ER) serves as the major intracellular calcium store. The release of calcium from this store regulates a variety of cellular functions, hence playing a key role in regulating apoptosis. The TMBIM6 is an evolutionarily conserved multifunctional ER membrane protein that mediates calcium homeostasis to protect against apoptosis and ER stress. Here we study a bacterial homolog of TMBIM6 and report several previously unidentified conformational substates involved in the calcium transport process.

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Why is it important?

BsYetJ is a bacterial homolog of transmembrane BAX inhibitor-1 motif-containing 6 (TMBIM6) membrane protein that plays a key role in the control of calcium homeostasis. However, the BsYetJ (or TMBIM6) structure embedded in a lipid bilayer is uncharacterized, let alone the molecular mechanism of the calcium transport activity. Herein, we report structures of BsYetJ in lipid nanodiscs identified by double electron-electron resonance spectroscopy. Our results reveal that BsYetJ in lipid nanodiscs is structurally different from those crystalized in detergents. We show that BsYetJ conformation is pH-sensitive in apo state (lacking calcium), whereas in a calcium-containing solution it is stuck in an intermediate, inert to pH changes. Only when the transmembrane calcium gradient is established can the calcium-release activity of holo-BsYetJ occur and be mediated by pH-dependent conformational changes, suggesting a dual gating mechanism. New conformational substates involved in the process are identified. Our study suggests that BsYetJ/TMBIM6 is a pH-dependent, voltage-gated calcium channel.


Our findings stimulate a model of calcium release channel showing that membrane protein functioning requires the interconversion between distinct conformations in preexisting conformational equilibria.

Yun-Wei Chiang
National Tsing Hua University

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This page is a summary of: Structure and regulation of the BsYetJ calcium channel in lipid nanodiscs, Proceedings of the National Academy of Sciences, November 2020, Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.2014094117.
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