Physiological and Pathological Functions of TMEM30A: An Essential Subunit of P4-ATPase Phospholipid Flippases

Figure 1

Phospholipid transport cycle of ATP8A1-TMEM30A flippase. Cell membranes are shown in gray, TMEM30A is shown in slate blue, ATP8A1 is boxed, and its four domains are shown in different colors (TM: transmembrane; A: actuator; P: phosphorylation; N: nucleotide-binding). The six intermediate states of ATP8A1-TMEM30A are arranged clockwise: E1, E1-ATP, E1P-ADP, E1P, E2P, and E2Pi-PL. Binding and hydrolysis of ATP trigger the transition of ATP8A1 from state E1 to E1-ATP and then to E1P-ADP. The subsequent phosphoryl transfer reaction induces the N and P domains proximally arrange after ATP binding at the N-domain, with a light outward shift of the A-domain. TMEM30A and the TM domain of ATP8A1 adopt almost the same conformation in all of these states. In E2P state, the N-domain is separated from the P domain and no longer accesses the phosphorylation site, while the A-domain is tightly fixed to the phosphorylation site, resulting in ADP-insensitivity. In the E2Pi-PL state, the P domain is phosphorylated, and phospholipid is released. Finally, ATP8A1 returns to the E1 state. Cyto: cytoplasmic side; Exo: exoplasmic side. PDBID: E1: 6K7H; E1-ATP: 6K7I; E1P-ADP: 6K7K; E1P: 6K7N; E2P: 6K7I; E2Pi-PL: 6K7M.