All-atom Simulations Uncover the Molecular Terms of NKCC1 Transport Mechanism

Abstract

AbstractThe secondary-active Na-K-Cl Cotransporter 1 (NKCC1), member of the Cation Chloride Cotransporters (CCC) family, ensures the electroneutral movement of Cl-, Na+, K+ ions across cellular membranes. NKCC1 regulates Cl- homeostasis and cell volume, handling a pivotal role in transepithelial water transport and neuronal excitability. Aberrant NKCC1 transport is hence implicated in a variety of human diseases (hypertension, renal disorders, neuropathies, cancer). Building on the newly-resolved NKCC1 cryo-EM structure, all-atom enhanced sampling simulations unprecedentedly unlock the mechanism of NKCC1-mediated ions transport, assessing the order and the molecular basis of its interdependent ions translocation. Our outcomes strikingly advance the understanding of the physiological mechanism of CCCs transporters and disclose a key role of CCC-conserved asparagine residues, whose side-chain promiscuity ensures the transport of both negatively and positively charged ions along the same translocation route. This study sets a conceptual basis to devise NKCC-selective inhibitors to treat diseases linked to Cl- dishomeostasis.Abstract Figure