8DIZ

Crystal structure of NavAb I119T as a basis for the human Nav1.7 Inherited Erythromelalgia I234T mutation

8DIZ の概要

• エントリーDOI: 10.2210/pdb8diz/pdb
• 分子名称: Ion transport protein, 1,2-DIMYRISTOYL-SN-GLYCERO-3-PHOSPHOCHOLINE (2 entities in total)
• 機能のキーワード: voltage-gated sodium channel ion transport protein, membrane protein
• 由来する生物種: Aliarcobacter butzleri RM4018
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33171.94

構造登録者

Wisedchaisri, G.,Gamal El-Din, T.M.,Zheng, N.,Catterall, W.A. (登録日: 2022-06-29, 公開日: 2023-04-12, 最終更新日: 2023-10-25)

主引用文献

Wisedchaisri, G.,Gamal El-Din, T.M.,Zheng, N.,Catterall, W.A.
Structural basis for severe pain caused by mutations in the S4-S5 linkers of voltage-gated sodium channel Na V 1.7.
Proc.Natl.Acad.Sci.USA, 120:e2219624120-e2219624120, 2023

PubMed Abstract: Gain-of-function mutations in voltage-gated sodium channel Na1.7 cause severe inherited pain syndromes, including inherited erythromelalgia (IEM). The structural basis of these disease mutations, however, remains elusive. Here, we focused on three mutations that all substitute threonine residues in the alpha-helical S4-S5 intracellular linker that connects the voltage sensor to the pore: Na1.7/I234T, Na1.7/I848T, and Na1.7/S241T in order of their positions in the amino acid sequence within the S4-S5 linkers. Introduction of these IEM mutations into the ancestral bacterial sodium channel NaAb recapitulated the pathogenic gain-of-function of these mutants by inducing a negative shift in the voltage dependence of activation and slowing the kinetics of inactivation. Remarkably, our structural analysis reveals a common mechanism of action among the three mutations, in which the mutant threonine residues create new hydrogen bonds between the S4-S5 linker and the pore-lining S5 or S6 segment in the pore module. Because the S4-S5 linkers couple voltage sensor movements to pore opening, these newly formed hydrogen bonds would stabilize the activated state substantially and thereby promote the 8 to 18 mV negative shift in the voltage dependence of activation that is characteristic of the Na1.7 IEM mutants. Our results provide key structural insights into how IEM mutations in the S4-S5 linkers may cause hyperexcitability of Na1.7 and lead to severe pain in this debilitating disease.

PubMed: 36996107
DOI: 10.1073/pnas.2219624120

実験手法

X-RAY DIFFRACTION (2.75 Å)