Conformational dynamics of the BsYetJ calcium transporter is finally revealed

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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Photo by National Cancer Institute on Unsplash

Photo by National Cancer Institute on Unsplash

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.

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