Aldolase provides an unusual binding site for thrombospondin-related anonymous protein in the invasion machinery of the malaria parasite

Jürgen Bosch, Carlos A. Buscaglia, Brian Krumm, Bjarni P. Ingason, Robert Lucas, Claudia Roach, Timothy Cardozo, Victor Nussenzweig, Wim G J Hol

Research output: Contribution to journalArticlepeer-review

64 Scopus citations


An actomyosin motor located underneath the plasma membrane drives motility and host-cell invasion of apicomplexan parasites such as Plasmodium falciparum and Plasmodium vivax, the causative agents of malaria. Aldolase connects the motor actin filaments to transmembrane adhesive proteins of the thrombospondin-related anonymous protein (TRAP) family and transduces the motor force across the parasite surface. The TRAP-aldolase interaction is a distinctive and critical trait of host hepatocyte invasion by Plasmodium sporozoites, with a likely similar interaction crucial for erythrocyte invasion by merozoites. Here, we describe 2.4-Å and 2.7-Å structures of P. falciparum aldolase (PfAldo) obtained from crystals grown in the presence of the C-terminal hexapeptide of TRAP from Plasmodium berghei. The indole ring of the critical penultimate Trp-residue of TRAP fits snugly into a newly formed hydrophobic pocket, which is exclusively delimited by hydrophilic residues: two arginines, one glutamate, and one glutamine. Comparison with the unliganded PfAldo structure shows that the two arginines adopt new side-chain rotamers, whereas a 25-residue subdomain, forming a helix-loop-helix unit, shifts upon binding the TRAP-tail. The structural data are in agreement with decreased TRAP binding after mutagenesis of PfAldo residues in and near the induced TRAP-binding pocket. Remarkably, the TRAP- and actin-binding sites of PfAldo seem to overlap, suggesting that both the plasticity of the aldolase active-site region and the multimeric nature of the enzyme are crucial for its intriguing nonenzymatic function in the invasion machinery of the malaria parasite.

Original languageEnglish (US)
Pages (from-to)7015-7020
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number17
StatePublished - Apr 24 2007
Externally publishedYes


  • Actin
  • Apicomplexa
  • Cell invasion machinery
  • Gliding motility
  • Induced fit

ASJC Scopus subject areas

  • Genetics
  • General


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