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Cation Chloride Cotransporter NKCC1 Operates through a Rocking-Bundle Mechanism
Manuel José Ruiz Munevar1, Valerio Rizzi2, Corinne Portioli3,4
1Laboratory of Molecular Modelling & Drug Discovery, Istituto Italiano di Tecnologia, Via Morego 30, Genoa 16163, Italy.
Journal of the American Chemical Society
|December 26, 2023
Summary
The sodium, potassium, and chloride cotransporter 1 (NKCC1) undergoes conformational changes crucial for its function. These dynamics, involving specific transmembrane helices, regulate ion and water transport, offering new therapeutic targets for neurological disorders and cancers.
Area of Science:
- Biophysics
- Molecular Biology
- Pharmacology
Background:
- The sodium, potassium, and chloride cotransporter 1 (NKCC1) is vital for ion transport across cell membranes.
- Aberrant NKCC1 activity is implicated in neurological disorders and cancers, making it a key therapeutic target.
Purpose of the Study:
- To elucidate the dynamic conformational motions of NKCC1 essential for its transport function.
- To understand NKCC1's role in ion and water permeability for potential therapeutic modulation.
Main Methods:
- Deep-learning-guided atomistic simulations of NKCC1 embedded in a membrane.
- Analysis of conformational transitions and water-permeable states.
- Mutagenesis experiments to validate identified functional residues.
Main Results:
- Identified a rocking-bundle mechanism involving TM4, TM9, and TM10 in NKCC1 conformational changes.
- Demonstrated NKCC1 possesses water-permeable states through specific conformational transitions.
- Discovered critical interhelical contacts between TM10 and TM6, functionally validated by mutagenesis.
Conclusions:
- NKCC1's function is modulated by specific conformational motions, particularly the rocking-bundle mechanism.
- Conserved residues identified in TM10 and TM6 are critical for NKCC1's ion and water transport.
- These findings pave the way for novel therapeutic strategies targeting NKCC1 and related cotransporters.
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