Quaternary structure independent folding of voltage-gated ion channel pore domain subunits

• Published in: Nature structural & molecular biology Vol. 29; no. 6; pp. 537 - 548
• Main Authors: Arrigoni, Cristina, Lolicato, Marco, Shaya, David, Rohaim, Ahmed, Findeisen, Felix, Fong, Lam-Kiu, Colleran, Claire M, Dominik, Pawel, Kim, Sangwoo S, Schuermann, Jonathan P, DeGrado, William F, Grabe, Michael, Kossiakoff, Anthony A, Minor, Jr, Daniel L
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.06.2022
• Subjects: BASIC BIOLOGICAL SCIENCES; Canonical forms; Crystal structure; Domains; Ion channels; membrane biophysics; Molecular Conformation; Molecular dynamics; Molecular Dynamics Simulation; Protein structure; Proteins; Quaternary structure; Sodium channels (voltage-gated); Subunit structure; Tertiary structure; Voltage-Gated Sodium Channels - chemistry; Voltage-Gated Sodium Channels - metabolism; x-ray crystallography
• ISSN: 1545-9993; 1545-9985
• DOI: 10.1038/s41594-022-00775-x

Every voltage-gated ion channel (VGIC) has a pore domain (PD) made from four subunits, each comprising an antiparallel transmembrane helix pair bridged by a loop. The extent to which PD subunit structure requires quaternary interactions is unclear. Here, we present crystal structures of a set of bacterial voltage-gated sodium channel (BacNa ) 'pore only' proteins that reveal a surprising collection of non-canonical quaternary arrangements in which the PD tertiary structure is maintained. This context-independent structural robustness, supported by molecular dynamics simulations, indicates that VGIC-PD tertiary structure is independent of quaternary interactions. This fold occurs throughout the VGIC superfamily and in diverse transmembrane and soluble proteins. Strikingly, characterization of PD subunit-binding Fabs indicates that non-canonical quaternary PD conformations can occur in full-length VGICs. Together, our data demonstrate that the VGIC-PD is an autonomously folded unit. This property has implications for VGIC biogenesis, understanding functional states, de novo channel design, and VGIC structural origins.