Identification of a nuclear localization signal in the Plasmodium falciparum CTP: phosphocholine cytidylyltransferase enzyme

Sci Rep. 2020 Nov 12;10(1):19739. doi: 10.1038/s41598-020-76829-1.

Abstract

The phospholipid biosynthesis of the malaria parasite, Plasmodium falciparum is a key process for its survival and its inhibition is a validated antimalarial therapeutic approach. The second and rate-limiting step of the de novo phosphatidylcholine biosynthesis is catalysed by CTP: phosphocholine cytidylyltransferase (PfCCT), which has a key regulatory function within the pathway. Here, we investigate the functional impact of the key structural differences and their respective role in the structurally unique pseudo-heterodimer PfCCT protein in a heterologous cellular context using the thermosensitive CCT-mutant CHO-MT58 cell line. We found that a Plasmodium-specific lysine-rich insertion within the catalytic domain of PfCCT acts as a nuclear localization signal and its deletion decreases the nuclear propensity of the protein in the model cell line. We further showed that the putative membrane-binding domain also affected the nuclear localization of the protein. Moreover, activation of phosphatidylcholine biosynthesis by phospholipase C treatment induces the partial nuclear-to-cytoplasmic translocation of PfCCT. We additionally investigated the cellular function of several PfCCT truncated constructs in a CHO-MT58 based rescue assay. In absence of the endogenous CCT activity we observed that truncated constructs lacking the lysine-rich insertion, or the membrane-binding domain provided similar cell survival ratio as the full length PfCCT protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CHO Cells
  • Catalytic Domain
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism*
  • Choline-Phosphate Cytidylyltransferase / chemistry*
  • Choline-Phosphate Cytidylyltransferase / genetics
  • Choline-Phosphate Cytidylyltransferase / metabolism*
  • Cricetinae
  • Cricetulus
  • Cytidine Triphosphate / metabolism
  • Nuclear Localization Signals*
  • Phosphorylcholine / metabolism
  • Plasmodium falciparum / enzymology*
  • Protein Binding
  • Protozoan Proteins / chemistry*
  • Protozoan Proteins / metabolism*
  • Sequence Homology, Amino Acid

Substances

  • Nuclear Localization Signals
  • Protozoan Proteins
  • Phosphorylcholine
  • Cytidine Triphosphate
  • Choline-Phosphate Cytidylyltransferase