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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| Published in: | Proceedings of the National Academy of Sciences - PNAS Vol. 121; no. 9; p. e2322899121 |
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| Main Authors: | , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
27.02.2024
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| ISSN: | 1091-6490 |
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| Abstract | 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. |
|---|---|
| AbstractList | 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. |
| Author | Huang, Gaoxingyu Li, Jiaao Pan, Xiaojing Li, Zhangqiang Yan, Nieng Jin, Xueqin Wu, Qiurong |
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| Keywords | structure–function relationship electromechanical coupling voltage-gated sodium channel closed-state inactivation cryo-EM |
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| Snippet | Voltage-gated sodium channels (Na
) undergo conformational shifts in response to membrane potential changes, a mechanism known as the electromechanical... |
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| SubjectTerms | Humans Membrane Potentials Mutation Structure-Activity Relationship Voltage-Gated Sodium Channels - genetics |
| Title | Dissection of the structure-function relationship of Na v channels |
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