Cryo-EM structure of the human NKCC1 transporter reveals mechanisms of ion coupling and specificity.

Autor: Neumann C; Danish Research Institute of Translational Neuroscience-DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Aarhus, Denmark.; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark., Rosenbaek LL; Department of Biomedicine, Aarhus University, Aarhus, Denmark., Flygaard RK; Danish Research Institute of Translational Neuroscience-DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Aarhus, Denmark.; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark., Habeck M; Danish Research Institute of Translational Neuroscience-DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Aarhus, Denmark.; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark., Karlsen JL; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark., Wang Y; Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen, Denmark.; Shanghai Institute for Advanced Study, Institute of Quantitative Biology, College of Life Sciences, Zhejiang University, Hangzhou, China., Lindorff-Larsen K; Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen, Denmark., Gad HH; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark., Hartmann R; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark., Lyons JA; Danish Research Institute of Translational Neuroscience-DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Aarhus, Denmark.; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.; Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus, Denmark., Fenton RA; Department of Biomedicine, Aarhus University, Aarhus, Denmark., Nissen P; Danish Research Institute of Translational Neuroscience-DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Aarhus, Denmark.; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
Jazyk: angličtina
Zdroj: The EMBO journal [EMBO J] 2022 Dec 01; Vol. 41 (23), pp. e110169. Date of Electronic Publication: 2022 Oct 14.
DOI: 10.15252/embj.2021110169
Abstrakt: The sodium-potassium-chloride transporter NKCC1 of the SLC12 family performs Na + -dependent Cl - - and K + -ion uptake across plasma membranes. NKCC1 is important for regulating cell volume, hearing, blood pressure, and regulation of hyperpolarizing GABAergic and glycinergic signaling in the central nervous system. Here, we present a 2.6 Å resolution cryo-electron microscopy structure of human NKCC1 in the substrate-loaded (Na + , K + , and 2 Cl - ) and occluded, inward-facing state that has also been observed for the SLC6-type transporters MhsT and LeuT. Cl - binding at the Cl1 site together with the nearby K + ion provides a crucial bridge between the LeuT-fold scaffold and bundle domains. Cl - -ion binding at the Cl2 site seems to undertake a structural role similar to conserved glutamate of SLC6 transporters and may allow for Cl - -sensitive regulation of transport. Supported by functional studies in mammalian cells and computational simulations, we describe a putative Na + release pathway along transmembrane helix 5 coupled to the Cl2 site. The results provide insight into the structure-function relationship of NKCC1 with broader implications for other SLC12 family members.
(©2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)
Databáze: MEDLINE
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