Dynamics of activation in the voltage-sensing domain of Ciona intestinalis phosphatase Ci-VSP.

TitleDynamics of activation in the voltage-sensing domain of Ciona intestinalis phosphatase Ci-VSP.
Publication TypeJournal Article
Year of Publication2024
AuthorsGuo SC, Shen R, Roux B, Dinner AR
JournalNat Commun
Date Published2024 Feb 15
KeywordsAnimals, Ciona intestinalis, Membrane Potentials, Membrane Proteins, Molecular Dynamics Simulation, Phosphoric Monoester Hydrolases

The Ciona intestinalis voltage-sensing phosphatase (Ci-VSP) is a membrane protein containing a voltage-sensing domain (VSD) that is homologous to VSDs from voltage-gated ion channels responsible for cellular excitability. Previously published crystal structures of Ci-VSD in putative resting and active conformations suggested a helical-screw voltage sensing mechanism in which the S4 helix translocates and rotates to enable exchange of salt-bridge partners, but the microscopic details of the transition between the resting and active conformations remained unknown. Here, by combining extensive molecular dynamics simulations with a recently developed computational framework based on dynamical operators, we elucidate the microscopic mechanism of the resting-active transition at physiological membrane potential. Sparse regression reveals a small set of coordinates that distinguish intermediates that are hidden from electrophysiological measurements. The intermediates arise from a noncanonical helical-screw mechanism in which translocation, rotation, and side-chain movement of the S4 helix are only loosely coupled. These results provide insights into existing experimental and computational findings on voltage sensing and suggest ways of further probing its mechanism.

Alternate JournalNat Commun
PubMed ID38360718
PubMed Central IDPMC10869754
Grant ListR01 GM062342 / GM / NIGMS NIH HHS / United States
R01 GM116961 / GM / NIGMS NIH HHS / United States
R35 GM136381 / GM / NIGMS NIH HHS / United States
S10 OD028655 / OD / NIH HHS / United States