Structural insights into the opening mechanism of human Cx43/GJA1 gap junction channel
Listed in
This article is not in any list yet, why not save it to one of your lists.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.