ATP4 (PfATP4, PF3D7_1211900, UniProt A0A143ZZK9) - curation notes

Automated deep research was unavailable in this environment (Falcon auth failure,
invalid OpenAI key). These notes are a manual literature review based on the UniProt
record and the cached full-text/abstract publications in publications/.

Identity and family

• 1264 aa P2-type (cation transport, TC 3.A.3) ATPase with N (nucleotide-binding), P
  (phosphorylation, PROSITE PS00154 DKTGT motif) and A (actuator) domains and a
  10-helix transmembrane domain. PANTHER PTHR43294:SF20 (Na+/K+-ATPase alpha
  superfamily). UniProt (Swiss-Prot, reviewed 2024) names it "P-type
  sodium-transporting ATPase4", EC 7.2.2.3.
• Historically annotated as a Ca2+-ATPase. Dyer et al. 1996 cloned it as PfATPase4 and
  judged it "most analogous to Ca2+ ATPases of the endoplasmic reticulum"
  PMID:8813672.
  Krishna et al. 2001 expressed it in Xenopus oocytes and reported a Ca2+-dependent
  ATPase activity PMID:11145964 (abstract only).
• That Ca2+ assignment was not confirmed: PMID:23414762
  Spillman et al. explain the history: ENA Na+-ATPases are close relatives of SERCA/PMCA
  PMID:23414762.

Function: Na+ efflux pump of the parasite plasma membrane

• Spillman et al. 2013 (Cell Host Microbe): intraerythrocytic parasites sit in a
  high-Na+ host cytosol (because of the new permeability pathways) and keep cytosolic
  Na+ low by ATP-dependent efflux via PfATP4; spiroindolones disrupt this and
  resistance mutations in PfATP4 attenuate the effect
  PMID:23414762.
  Inhibition causes Na+-dependent cytosolic alkalinisation, which led to the proposal
  that PfATP4 imports H+ in exchange for Na+ (not directly demonstrated).
• Rosling et al. 2018 (JBC): Na+-dependent, cipargamin-sensitive ATPase activity in
  parasite membranes; Km(Na+) ~16 mM, Km(ATP) 0.23 mM; insensitive to K+ and Ca2+
  PMID:29986883
  PMID:29986883
  Plasma membrane location PMID:29986883.
• Qiu et al. 2022 (Nat Commun): G358S clinical resistance mutation reduces Na+ affinity,
  raises resting [Na+]cyt; equivalent mutation in T. gondii ATP4 behaves similarly
  PMID:36180431.
• Many chemically distinct antimalarials (spiroindolones/cipargamin PMID:20813948,
  aminopyrazoles PMID:25322084, dihydroisoquinolones/(+)-SJ733 PMID:25453091,
  4-cyano-3-methylisoquinolines PMID:31311978) select resistance mutations in PfATP4.
  Inhibition leads to Na+ accumulation and osmotic swelling of the parasite
  PMID:29555632
  and, for (+)-SJ733, eryptosis-driven host clearance of infected erythrocytes
  PMID:25453091.
  The host-clearance effect is a downstream drug consequence, not a function of PfATP4.

Structure (2025)

• Haile et al. 2025 (Nat Commun): 3.7 A cryo-EM structure of endogenous PfATP4 from
  CRISPR-tagged parasites; SERCA-like ion-binding site with conserved Na+-coordinating
  residues PMID:41115914;
  discovery of an apicomplexan-specific partner PfABP needed for PfATP4 stability
  PMID:41115914.

Annotation calls (summary)

• ACCEPT: P-type sodium transporter activity (IBA, IEA); plasma membrane (IBA, IEA).
• MODIFY to GO:0036376 sodium ion export across plasma membrane: sodium ion transport
  (IBA), sodium ion transmembrane transport (IEA), monoatomic ion transmembrane transport
  (IBA, IEA). membrane -> plasma membrane. nucleotide binding -> ATP binding.
  ATP hydrolysis activity -> P-type sodium transporter activity (transporter activity
  subsumes the coupled hydrolysis).
• KEEP_AS_NON_CORE: ATP binding.
• REMOVE: P-type potassium transmembrane transporter activity, potassium ion transport,
  potassium ion transmembrane transport (K+ has no effect on PfATP4 activity; no
  evidence of K+ transport); intracellular calcium ion homeostasis (Ca2+ ATPase
  assignment unconfirmed and superseded; activity insensitive to Ca2+).
• NEW: GO:0006883 intracellular sodium ion homeostasis (PfATP4 itself extrudes the Na+;
  participation, not just necessity).

Open questions

• Is H+ the counter-transported ion (Na+/H+-ATPase stoichiometry)?
• Does PfABP act as a beta-subunit-like chaperone or a regulator of turnover?
• Role in mosquito / liver stages (Na+ environment differs).