Structural insights into the opening mechanism of human Cx43/GJA1 gap junction channel

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Abstract

Gating of the gap junction intercellular channel (GJCh) is tightly regulated by several cellular factors; however, the underlying mechanism is poorly understood. A cryo-EM study of human Cx43 GJCh revealed detailed structural changes induced by PIP 2 . Cx43 protomers in a phospholipid environment show dynamic equilibrium among several N-terminal helix (NTH) conformations, including gate-covering NTH (GCN) and pore-lining NTH (PLN). Upon treatment with a water-soluble PIP 2 analog, the conformational equilibrium shifted from GCN to PLN in a dose-dependent manner, resulting in a decrease in the pore-occluding density and an increase in the open probability. The PIP 2 head interacts closely with basic residues in the membrane opening between neighboring protomers and the cytoplasmic loop (CL). These ionic interactions strengthen the binding of CL to a transmembrane helix, which consequently inhibits the GCN conformation through steric hindrance. This study provides structural insights into the mechanisms underlying the opening of Cx43 GJCh.

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