1. Structures and an activation mechanism of human potassium-chloride cotransporters
- Author
-
Jin Wang, Shenghai Chang, Sheng Ye, Feng Wang, Cheng Zhao, Si Liu, Jiangtao Guo, Eric Delpire, and Yuan Xie
- Subjects
Physiology ,Biophysics ,Peptide ,Neurotransmission ,Inhibitory postsynaptic potential ,03 medical and health sciences ,0302 clinical medicine ,Chlorides ,Humans ,Research Articles ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Multidisciplinary ,Symporters ,Chemistry ,Cell Membrane ,SciAdv r-articles ,Transporter ,Transmembrane domain ,Cytosol ,Potassium ,CTD ,Cotransporter ,030217 neurology & neurosurgery ,Research Article - Abstract
The full-length structures of human KCCs in an autoinhibition state suggest a potential activation mechanism., 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 γ-aminobutyric acid (GABA) and glycine-mediated inhibitory neurotransmission. Here, we present 2.9- to 3.6-Å 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.
- Published
- 2020