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

Abstract

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-A and 2.7-A 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.

• Authors: Jürgen Bosch, Carlos A Buscaglia, Brian Krumm, Bjarni P Ingason, Robert Lucas, Claudia Roach, Timothy Cardozo, Victor Nussenzweig, Wim G J Hol
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 104 Issue 17 Pg. 7015-20 (Apr 24 2007) ISSN: 0027-8424 [Print] United States
• PMID: 17426153 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Indoles
• Protozoan Proteins
• thrombospondin-related adhesive protein, protozoan
• indole
• Fructose-Bisphosphate Aldolase

Topics

• Amino Acid Sequence
• Amino Acid Substitution
• Animals
• Binding Sites
• Fructose-Bisphosphate Aldolase (chemistry, metabolism)
• Indoles (chemistry)
• Malaria, Falciparum (parasitology)
• Molecular Sequence Data
• Mutation (genetics)
• Plasmodium falciparum (enzymology, pathogenicity)
• Protein Binding
• Protein Structure, Secondary
• Protozoan Proteins (chemistry, metabolism)
• Substrate Specificity