6ALE

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

Summary for 6ALE

• Entry DOI: 10.2210/pdb6ale/pdb
• Descriptor: Small conductance calcium-activated potassium channel protein 2, Calmodulin-2, SULFATE ION, ... (7 entities in total)
• Functional Keywords: calcium binding protein, metal transport
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 28538.93

Authors

Nam, Y.W.,Zhang, M. (deposition date: 2017-08-07, release date: 2018-08-08, Last modification date: 2024-03-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.5 Å)