9VEO

structure of human KCNQ1-CaM-PIP2 complex with straight conformation

Summary for 9VEO

• Entry DOI: 10.2210/pdb9veo/pdb
• EMDB information: 65014
• Descriptor: Potassium voltage-gated channel subfamily KQT member 1, Calmodulin-1, [(2R)-1-octadecanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phospho ryl]oxy-propan-2-yl] (8Z)-icosa-5,8,11,14-tetraenoate, ... (4 entities in total)
• Functional Keywords: potassium channel complex, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 324452.62

Authors

Cui, C.,Kermani, A.,Cui, J.,Sun, J. (deposition date: 2025-06-09, release date: 2025-08-20, Last modification date: 2025-11-19)

Primary citation

Cui, C.,Zhao, L.,Kermani, A.A.,Du, S.,Pipatpolkai, T.,Jiang, M.,Chittori, S.,Tan, Y.Z.,Shi, J.,Delemotte, L.,Cui, J.,Sun, J.
Mechanisms of KCNQ1 gating modulation by KCNE1/3 for cell-specific function.
Cell Res., 35:876-886, 2025

PubMed Abstract: KCNQ1 potassium channels are essential for physiological processes such as cardiac rhythm and intestinal chloride secretion. KCNE family subunits (KCNE1-5) associate with KCNQ1, conferring distinct properties across various tissues. KCNQ1 activation requires membrane depolarization and phosphatidylinositol 4,5-bisphosphate (PIP2) whose cellular levels are controlled by Gαq-coupled GPCR activation. While modulation of KCNQ1's voltage-dependent activation by KCNE1/3 is well-characterized, their effects on PIP2-dependent gating of KCNQ1 via GPCR signaling remain less understood. Here we resolved structures of KCNQ1-KCNE1 and reassessed the reported KCNQ1-KCNE3 structures with and without PIP2. We revealed that KCNQ1-KCNE1/3 complexes feature two PIP2-binding sites, with KCNE1/3 contributing to a previously overlooked, uncharacterized site involving residues critical for coupling voltage sensor and pore domains. Via this site, KCNE1 and KCNE3 distinctly modulate the PIP2-dependent gating, in addition to the voltage sensitivity, of KCNQ1. Consequently, KCNE3 converts KCNQ1 into a voltage-insensitive PIP2-gated channel governed by GPCR signaling to maintain ion homeostasis in non-excitable cells. KCNE1, by significantly enhancing KCNQ1's PIP2 affinity and resistance to GPCR regulation, forms predominantly voltage-gated channels with KCNQ1 for conducting the slow-delayed rectifier current in excitable cardiac cells. Our study highlights how KCNE1/3 modulates KCNQ1 gating in different cellular contexts, providing insights into tissue-specifically targeting multi-functional channels.

PubMed: 40745202
DOI: 10.1038/s41422-025-01152-1

Experimental method

ELECTRON MICROSCOPY (3.7 Å)