Dissection of the structure-function relationship of Na v channels

Voltage-gated sodium channels (Na ) undergo conformational shifts in response to membrane potential changes, a mechanism known as the electromechanical coupling. To delineate the structure-function relationship of human Na channels, we have performed systematic structural analysis using human Na 1.7...

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Vydáno v:Proceedings of the National Academy of Sciences - PNAS Ročník 121; číslo 9; s. e2322899121
Hlavní autoři: Li, Zhangqiang, Wu, Qiurong, Huang, Gaoxingyu, Jin, Xueqin, Li, Jiaao, Pan, Xiaojing, Yan, Nieng
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 27.02.2024
Témata:
Humans
Membrane Potentials
Mutation
Structure-Activity Relationship
Voltage-Gated Sodium Channels - genetics
structure–function relationship
electromechanical coupling
voltage-gated sodium channel
closed-state inactivation
cryo-EM
ISSN:1091-6490
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Shrnutí:Voltage-gated sodium channels (Na ) undergo conformational shifts in response to membrane potential changes, a mechanism known as the electromechanical coupling. To delineate the structure-function relationship of human Na channels, we have performed systematic structural analysis using human Na 1.7 as a prototype. Guided by the structural differences between wild-type (WT) Na 1.7 and an eleven mutation-containing variant, designated Na 1.7-M11, we generated three additional intermediate mutants and solved their structures at overall resolutions of 2.9-3.4 Å. The mutant with nine-point mutations in the pore domain (PD), named Na 1.7-M9, has a reduced cavity volume and a sealed gate, with all voltage-sensing domains (VSDs) remaining up. Structural comparison of WT and Na 1.7-M9 pinpoints two residues that may be critical to the tightening of the PD. However, the variant containing these two mutations, Na 1.7-M2, or even in combination with two additional mutations in the VSDs, named Na 1.7-M4, failed to tighten the PD. Our structural analysis reveals a tendency of PD contraction correlated with the right shift of the static inactivation I-V curves. We predict that the channel in the resting state should have a "tight" PD with down VSDs.
ISSN:1091-6490
DOI:10.1073/pnas.2322899121