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

The 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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/443869v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@182ddaforg.highwire.dtl.DTLVardef@a83f33org.highwire.dtl.DTLVardef@1cd4012org.highwire.dtl.DTLVardef@296f14_HPS_FORMAT_FIGEXP M_FIG C_FIG