FIGURE 2.

Structural organization of human KCC2. 2-dimensional (left) and 3-dimensional (right) organization of human KCC2 according to Chi X. et al. (2020) (PDB: 6m23). KCC2 consists of 12 transmembrane domains (TMs) and two intracellular termini. A large extracellular loop is located between transmembrane domains 5 and 6 (EL3) and five N-glycosylation sites (blue cubes, left). Phosphorylation sites that increase KCC2 activity upon dephosphorylation are marked as green stars (Thr⁶ in KCC2a, Thr⁹⁰⁶, Tyr⁹⁰³, Thr¹⁰⁰⁷, Thr¹⁰⁰⁹, and Tyr¹⁰⁸⁷). Phosphorylation sites that increase KCC2 activity upon phosphorylation are marked as blue stars (Ser⁹³², Thr⁹³⁴, Ser⁹³⁷, Ser⁹⁴⁰). Human pathogenic variants of KCC2 associated with epilepsy, autism-spectrum disorder, and schizophrenia are depicted as red dots (Ala^191Val, Leu^311His, Trp^318Ser, Ser^323Pro, Leu^403Pro, Met^415Val, Gly^528Asp, Arg^952His, Arg^1048Trp, Arg^1049C, Ser^748del). Annotation of amino acid residues is according to human KCC2b. The 3D reconstruction of KCC2 was generated using cryo-EM (Chi X. et al., 2020). 3D visualization was performed using Mol* Viewer in PDB (Sehnal et al., 2021).