Structures and an activation mechanism of human potassium-chloride cotransporters
Open Access
- 30 November 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Advances
- Vol. 6 (50), eabc5883
- https://doi.org/10.1126/sciadv.abc5883
Abstract
Potassium-chloride cotransporters KCC1 to KCC4 mediate the coupled export of potassium and chloride across the plasma membrane and play important roles in cell volume regulation, auditory system function, and gamma-aminobutyric acid (GABA) and glycine-mediated inhibitory neurotransmission. Here, we present 2.9- to 3.6-angstrom resolution structures of full-length human KCC2, KCC3, and KCC4. All three KCCs adopt a similar overall architecture, a domain-swap dimeric assembly, and an inward-facing conformation. The structural and functional studies reveal that one unexpected N-terminal peptide binds at the cytosolic facing cavity and locks KCC2 and KCC4 at an autoinhibition state. The C-terminal domain (CTD) directly interacts with the N-terminal inhibitory peptide, and the relative motions between the CTD and the transmembrane domain (TMD) suggest that CTD regulates KCCs' activities by adjusting the autoinhibitory effect. These structures provide the first glimpse of full-length structures of KCCs and an autoinhibition mechanism among the amino acid-polyamine-organocation transporter superfamily.Funding Information
- National Institutes of Health (DK093501)
- National Institutes of Health (DK110375)
- National Natural Science Foundation of China (31870724)
- National Natural Science Foundation of China (31430019)
- Ministry of Science and Technology of the People’s Republic of China (2018YFA0508100)
- Ministry of Science and Technology of the People’s Republic of China (2016YFA0500404)
- Leducq Foundation (17CVD05)
- Laboratory and equipment management, Zhejiang University (SJS201814)
- Fundamental Research Funds for the Central Universities
- Zhejiang Provincial Natural Science Foundation (LR19C050002)
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