Skip to main content
. 2021 Jul 26;11(8):562. doi: 10.3390/membranes11080562

Figure 1.

Figure 1

(A) Fourteen human P4-ATPases are shown, each corresponding to a different homologous group. The α subunit is bound to the β subunit. The five P4-ATPases found on the green background all have PS or PE as a transport substrate. All three P4-ATPases on the orange background have PC as a substrate. Three P4-ATPases do not have a beta subunit. The 14 human P4-ATPases paired with their respective beta subunit [77,84,86,87,88,89,90,91] (B) Five S. cerevisiae P4-ATPases. Each P4-ATPase is paired with its respective beta subunit. The P4-ATPases on the green background all have PS or PE as a transport substrate. The P4-ATPases on the orange background have PC as a substrate [77,84,86,87,88,89,90,91]. (C) A structural model of P4-ATPase. The cytoplasmic domains are shown above. The nucleotide binding (N) is shown in yellow, the phosphorylation (P) is shown in blue, and the actuator (A) domain is shown in magenta. The 10 transmembrane helices (TM1-TM10) are shown in teal. The β subunit is shown in orange [42]. (D) Cellular signaling associated with P4-ATPases. ATP9A is a human P4-ATPase which flips phosphosphingolipids (PS) which has been shown to inhibit apoptosis, blood clotting, neuron pruning, and neurodegeneration [66,68,70]. The accumulation of PS on the cytosolic leaflet has also been shown to activate PIEZO1 downstream which governs morphogenesis during myotube formation [71]. PS accumulation on the luminal leaflet has been linked to budding in budding yeast and extracellular vesicles (EVs) [66,92]. ATP9A and ATP10A flip phosphatidylcholine (PC). The increased PC on the cytosolic leaflet has been shown to be a docking site for multivesicular late endosomes (MVE) [63]. High cytosolic leaflet PC concentration has been shown to inhibit actin nucleation, cell adhesion, and cell spreading [63,79]. ATP10A transports glucosylceramide (GlcCer) to the cytosolic leaflet which has been shown to inhibit insulin signaling [64]. Kes1p is an upstream oxysterol binding protein which targets P4-ATPases which antagonize Kes1p in return [58]. PS flippases such as ATP11C are autoinhibited, and phosphatidylinositol-4-phosphate (PI4P) inhibits the autoinhibition, i.e., reactivates the flippase [39,57]. PKCα activates ATP11C which leads to the internalization of the flippase through clathrin-mediated endocytosis [68,77,80,82,83]. P4-ATPases have also been implicated in the formation of lysosomes, ectosomes, and the endocytic recycling pathway [61,62,69].