Structural Basis of Phosphatidic Acid Sensing by APH in Apicomplexan Parasites

Structure. 2018 Aug 7;26(8):1059-1071.e6. doi: 10.1016/j.str.2018.05.001. Epub 2018 Jun 14.

Abstract

Plasmodium falciparum and Toxoplasma gondii are obligate intracellular parasites that belong to the phylum of Apicomplexa and cause major human diseases. Their access to an intracellular lifestyle is reliant on the coordinated release of proteins from the specialized apical organelles called micronemes and rhoptries. A specific phosphatidic acid effector, the acylated pleckstrin homology domain-containing protein (APH) plays a central role in microneme exocytosis and thus is essential for motility, cell entry, and egress. TgAPH is acylated on the surface of the micronemes and recruited to phosphatidic acid (PA)-enriched membranes. Here, we dissect the atomic details of APH PA-sensing hub and its functional interaction with phospholipid membranes. We unravel the key determinant of PA recognition for the first time and show that APH inserts into and clusters multiple phosphate head-groups at the bilayer binding surface.

Keywords: NMR; Plasmodium falciparum; Toxoplasma gondii; egress; exocytosis; gliding motility; invasion; microneme; phosphatidic acid; pleckstrin homology domain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acylation
  • Amino Acid Sequence
  • Cell Membrane / chemistry
  • Cell Membrane / metabolism
  • Cell Membrane / parasitology
  • Cloning, Molecular
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Exocytosis
  • Fibroblasts / metabolism
  • Fibroblasts / parasitology*
  • Gene Expression
  • Genetic Vectors / chemistry
  • Genetic Vectors / metabolism
  • Host-Parasite Interactions
  • Humans
  • Lipid Bilayers / chemistry
  • Lipid Bilayers / metabolism
  • Molecular Dynamics Simulation
  • Organelles / metabolism
  • Organelles / ultrastructure
  • Phosphatidic Acids / chemistry
  • Phosphatidic Acids / metabolism*
  • Plasmodium falciparum / genetics
  • Plasmodium falciparum / metabolism*
  • Plasmodium falciparum / ultrastructure
  • Pleckstrin Homology Domains
  • Primary Cell Culture
  • Protein Processing, Post-Translational*
  • Protozoan Proteins / chemistry*
  • Protozoan Proteins / genetics
  • Protozoan Proteins / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Toxoplasma / genetics
  • Toxoplasma / metabolism*
  • Toxoplasma / ultrastructure

Substances

  • Lipid Bilayers
  • Phosphatidic Acids
  • Protozoan Proteins
  • Recombinant Proteins