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An erythrocyte cytoskeleton-binding motif in exported Plasmodium falciparum proteins

Geoffrey K Kilili1, Douglas J LaCount

  • 1Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.

Eukaryotic Cell
|September 13, 2011
PubMed

Insights

The malaria parasite Plasmodium falciparum exports proteins that alter red blood cells. A key binding domain (MEC) is found in multiple exported proteins, enabling interaction with the erythrocyte cytoskeleton and protein 4.1R.

Area of Science:

  • Malariology
  • Cell Biology
  • Protein Interactions

Background:

  • Exported malaria parasite proteins induce significant changes in Plasmodium falciparum-infected erythrocytes.
  • The mature parasite-infected erythrocyte surface antigen (MESA) interacts with erythrocyte protein 4.1R via a specific sequence, targeting the host cytoskeleton.

Purpose of the Study:

  • To identify and characterize the MESA erythrocyte cytoskeleton-binding (MEC) domain in other exported Plasmodium falciparum proteins.
  • To investigate the functional significance of a conserved C-terminal aspartic acid within the MEC domain.

Main Methods:

  • Sequence alignment of putative cytoskeleton-binding domains from P. falciparum proteins.
  • Site-directed mutagenesis to assess the role of the C-terminal aspartic acid.
  • Pulldown assays using erythrocyte inside-out vesicles (IOVs) and purified protein fragments.
  • Coprecipitation assays to examine interactions with erythrocyte cytoskeleton components, including protein 4.1R.

Main Results:

  • The MEC domain is present in at least 13 P. falciparum proteins predicted to be exported.
  • A conserved C-terminal aspartic acid is crucial for optimal MESA binding to IOVs.
  • Seven P. falciparum proteins containing the MEC domain demonstrated binding to IOVs, with MESA exhibiting the highest affinity.
  • MESA, PF10_0378, and PFA0675w proteins interacted with and coprecipitated full-length protein 4.1R.

Conclusions:

  • The MEC motif is a conserved and functional domain in multiple Plasmodium falciparum proteins exported to the host cell.
  • These findings reveal a broader mechanism by which malaria parasites manipulate the erythrocyte cytoskeleton through various exported proteins.
  • The identified interactions highlight potential targets for antimalarial drug development.

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