6ALE

A V-to-F substitution in SK2 channels causes Ca2+ hypersensitivity and improves locomotion in a C. elegans ALS model

6ALE の概要

• エントリーDOI: 10.2210/pdb6ale/pdb
• 分子名称: Small conductance calcium-activated potassium channel protein 2, Calmodulin-2, SULFATE ION, ... (7 entities in total)
• 機能のキーワード: calcium binding protein, metal transport
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 28538.93

構造登録者

Nam, Y.W.,Zhang, M. (登録日: 2017-08-07, 公開日: 2018-08-08, 最終更新日: 2024-03-13)

主引用文献

Nam, Y.W.,Baskoylu, S.N.,Gazgalis, D.,Orfali, R.,Cui, M.,Hart, A.C.,Zhang, M.
A V-to-F substitution in SK2 channels causes Ca2+hypersensitivity and improves locomotion in a C. elegans ALS model.
Sci Rep, 8:10749-10749, 2018

PubMed Abstract: Small-conductance Ca-activated K (SK) channels mediate medium afterhyperpolarization in the neurons and play a key role in the regulation of neuronal excitability. SK channels are potential drug targets for ataxia and Amyotrophic Lateral Sclerosis (ALS). SK channels are activated exclusively by the Ca-bound calmodulin. Previously, we identified an intrinsically disordered fragment that is essential for the mechanical coupling between Ca/calmodulin binding and channel opening. Here, we report that substitution of a valine to phenylalanine (V407F) in the intrinsically disordered fragment caused a ~6 fold increase in the Ca sensitivity of SK2-a channels. This substitution resulted in a novel interaction between the ectopic phenylalanine and M411, which stabilized PIP-interacting residue K405, and subsequently enhanced Ca sensitivity. Also, equivalent valine to phenylalanine substitutions in SK1 or SK3 channels conferred Ca hypersensitivity. An equivalent phenylalanine substitution in the Caenorhabditis elegans (C. elegans) SK2 ortholog kcnl-2 partially rescued locomotion defects in an existing C. elegans ALS model, in which human SOD1G85R is expressed at high levels in neurons, confirming that this phenylalanine substitution impacts channel function in vivo. This work for the first time provides a critical reagent for future studies: an SK channel that is hypersensitive to Ca with increased activity in vivo.

PubMed: 30013223
DOI: 10.1038/s41598-018-28783-2

実験手法

X-RAY DIFFRACTION (2.5 Å)