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Markov modeling reveals novel intracellular modulation of the human TREK-2 selectivity filter

Two-pore domain potassium (K2P) channel ion conductance is regulated by diverse stimuli that directly or indirectly gate the channel selectivity filter (SF). Recent crystal structures for the TREK-2 member of the K2P family reveal distinct “up” and “down” states assumed during activation via mechani...

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Detalles Bibliográficos
Autores principales: Harrigan, Matthew P., McKiernan, Keri A., Shanmugasundaram, Veerabahu, Denny, Rajiah Aldrin, Pande, Vijay S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428000/
https://www.ncbi.nlm.nih.gov/pubmed/28377596
http://dx.doi.org/10.1038/s41598-017-00256-y
Descripción
Sumario:Two-pore domain potassium (K2P) channel ion conductance is regulated by diverse stimuli that directly or indirectly gate the channel selectivity filter (SF). Recent crystal structures for the TREK-2 member of the K2P family reveal distinct “up” and “down” states assumed during activation via mechanical stretch. We performed 195 μs of all-atom, unbiased molecular dynamics simulations of the TREK-2 channel to probe how membrane stretch regulates the SF gate. Markov modeling reveals a novel “pinched” SF configuration that stretch activation rapidly destabilizes. Free-energy barrier heights calculated for critical steps in the conduction pathway indicate that this pinched state impairs ion conduction. Our simulations predict that this low-conductance state is accessed exclusively in the compressed, “down” conformation in which the intracellular helix arrangement allosterically pinches the SF. By explicitly relating structure to function, we contribute a critical piece of understanding to the evolving K2P puzzle.