Fig. 1: Cryo-EM analysis of human ATP13A2.

a Schematic diagram of Post-Albers cycle for ATP13A2. The transport of SPM is shown in blue. Components that mimic the enzyme intermediates of their respective reaction cycles are shown in red. SPM (marked in blue) is recruited from the lumen side of ATP13A2 in the E2P state and released into the cytoplasm in the E2 state. b Topology diagram of hATP13A2. Conserved domains and TM helices are schematically illustrated. In the cytoplasmic regions, the A, N, and P domains and the C-terminal regulatory ___domain (CTD) are colored marine, pale violet red, limegreen, and medium purple, respectively. TM1-TM2, TM3-TM5, and TM6-TM10 of ATP13A2 are cyan, magenta, and salmon. The specific N-terminal ___domain (NTD) is colored in pink. The DKTG motif in the P-___domain, the KGSPE motif in the N-___domain, the TGE motif in the A ___domain, and TM4 is divided into TM4a and TM4b. c Cryo-EM density map of hATP13A2 in the E1-ATP state. d Atomic models of hATP13A2 in six intermediate states along the Post-Albers transporting cycle: E1-like, E1-ATP, E1P-ADP, E2P, E2-Pi, and putative E2. The SPM is shown as spheres models. e The AMP-PCP molecule tightly bound to the catalytic center in the E1-ATP state. The AMP-PCP nucleotide is shown in blue sticks, and Mg²⁺ ions are shown as orange spheres. The distribution of conserved motifs on the A, N, and P domains are marked by dashed boxes in marine, pale violet red, and limegreen, respectively. f–h The key signature motifs KGSPE for ATP coordination within N-___domain (f), DKTG for auto-phosphorylation within P-___domain (g), TGE for dephosphorylation within A-___domain (h). Key residues are represented as colored sticks with labels. The same color scheme is used throughout the manuscript.