Structural Basis of Human KCNQ1 Modulation and Gating

• Published in: Cell Vol. 180; no. 2; pp. 340 - 347.e9
• Main Authors: Sun, Ji, MacKinnon, Roderick
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.01.2020
• Subjects: cryo-electron microscopy; Cryoelectron Microscopy; electric potential difference; functional properties; gastric acid; glucose; heart; homeostasis; Humans; ion channel gating; Ion Channel Gating - physiology; ion channel modulation; K channel beta-subunit; KCNE3; KCNQ1; KCNQ1 Potassium Channel - chemistry; KCNQ1 Potassium Channel - metabolism; KCNQ1 Potassium Channel - ultrastructure; lipids; long-QT syndromes; Membrane Potentials - physiology; Patch-Clamp Techniques; Phosphatidylinositol 4,5-Diphosphate - metabolism; PIP2; potassium channels; Potassium Channels, Voltage-Gated - chemistry; Potassium Channels, Voltage-Gated - metabolism; Potassium Channels, Voltage-Gated - ultrastructure; secretion; KCNE3; KCNQ1; K channel beta-subunit; ion channel modulation; ion channel gating; long-QT syndromes; PIP2
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2019.12.003

KCNQ1, also known as Kv7.1, is a voltage-dependent K+ channel that regulates gastric acid secretion, salt and glucose homeostasis, and heart rhythm. Its functional properties are regulated in a tissue-specific manner through co-assembly with beta subunits KCNE1–5. In non-excitable cells, KCNQ1 forms a complex with KCNE3, which suppresses channel closure at negative membrane voltages that otherwise would close it. Pore opening is regulated by the signaling lipid PIP2. Using cryoelectron microscopy (cryo-EM), we show that KCNE3 tucks its single-membrane-spanning helix against KCNQ1, at a location that appears to lock the voltage sensor in its depolarized conformation. Without PIP2, the pore remains closed. Upon addition, PIP2 occupies a site on KCNQ1 within the inner membrane leaflet, which triggers a large conformational change that leads to dilation of the pore’s gate. It is likely that this mechanism of PIP2 activation is conserved among Kv7 channels. [Display omitted] •Structures of human KCNQ1-CaM and KCNQ1-KCNE3-CaM complexes without PIP2•Structural mechanism of KCNQ1 modulation by KCNE3•Structure of human KCNQ1-KCNE3-CaM with PIP2•Gating mechanism of KCNQ1 by PIP2 Cryo-EM structures of the human voltage-dependent potassium channel KCNQ1 in complex with its ancillary subunit KCNE3, in the presence or absence of the PIP2-activating co-factor, provide insight into how PIP2 binding leads to channel opening.