Plasmodium falciparum P-type sodium ATPase 4 (PfATP4) (PfATP4)

Plasmodium falciparum ATP4 (PfATP4) is an essential P-type cation-transporting ATPase of the parasite plasma membrane that functions as a Na+ pump responsible for maintaining low cytosolic sodium and the transmembrane Na+ gradient crucial for parasite survival. It belongs to the type 2D subfamily of P-type ATPases and uses ATP hydrolysis to actively extrude Na+. Pharmacological inhibition of PfATP4 rapidly collapses Na+ homeostasis and triggers profound changes in parasite membrane lipid organization, including reversible accumulation of cholesterol in the parasite plasma membrane detectable as increased saponin sensitivity, leading to parasite death. PfATP4 has emerged as a high-value antimalarial target because mutations in pfatp4 confer resistance to diverse chemotypes (spiroindolones such as cipargamin/KAE609, pyrazoles, dihydroisoquinolones, and compounds from MMV’s Malaria Box), indicating that many next-generation antimalarials act through this pump. Recent genetic and cell-biological analyses reinforce its essential role and link PfATP4 function to broader membrane homeostasis pathways, including dependence of the Niemann-Pick C1-related transporter PfNCR1 on the Na+ gradient maintained by PfATP4.

Other names

P-type Na+ ATPase PfATP4Sodium-transporting P-type ATPase PfATP4Type 2D P-type ATPase (P2D ATPase)Na+ pump PfATP4

Inhibition of PfATP4 Na+ pumping activity, collapsing the Na+ gradient, disrupting Na+ homeostasis, and rapidly inducing lethal physiological changes including altered lipid/cholesterol distribution in the parasite plasma membrane