Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 29, Issue 6, Pages 537-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41594-022-00775-x
Keywords
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Funding
- NIH-NHLBI [R01-HL080050]
- NIH-NIDCD [R01-DC007664]
- Program for Breakthrough Biomedical Research - Sandler Foundation
- NIH-NIGMS [R35 GM122603, R21-GM100224, R01-GM137109, GM117372]
- AHA postdoctoral fellowships
- National Institute of General Medical Sciences from the National Institutes of Health [P30 GM124165]
- DOE Office of Science [DE-AC02-06CH11357]
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The subunit structure of the voltage-gated ion channel pore domain is independent of quaternary interactions, suggesting a context-independent structural robustness.
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(v)) '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.
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