The Hsp40 proteins of Plasmodium falciparum and other apicomplexa:: Regulating chaperone power in the parasite and the host

Extensive structural and functional remodelling of Plasmodittin falciparum (malaria)-infected erythrocytes follows the export of a range of proteins of parasite origin (exportome) across the parasitophorous vacuole into the host erythrocyte. The genome of P. falciparum encodes a diverse chaperone complement including at least 43 members of the heat shock protein 40 kDa (Hsp40) family, and six members of the heat shock protein 70 kDa (Hsp70) family. Nearly half of the Hsp40 proteins of P. falciparmn are predicted to contain a PEXEL/HT (Plasmodium export element/host targeting signal) sequence motif, and hence are likely to be part of the exportome. In this review we critically evaluate the classification, sequence similarity and clustering, and possible interactors of the P. fialciparum Hsp40 chaperone machinery. In addition to the types 1, 11 and 111 Hsp40 proteins all exhibiting the signature J-domain, the Pjalciparum genome also encodes a number of specialized Hsp40 proteins with a Mike domain, which we have categorized as type IV Hsp40 proteins. Analysis of the potential P.fialciparwn Hsp40 protein interaction network revealed connections predominantly with cytoskeletal and membrane proteins, transcriptional machinery, DNA repair and replication machinery, translational machinery, the proteasome and proteolytic enzymes, and enzymes involved in cellular physiology. Comparison of the Hsp40 proteins of P. ftilciparum to those of other apicomplexa reveals that most of the proteins (especially the PEXEL/HT-containing proteins) are unique to P.fialciparum. Furthermore, very few of the P.fialciparum Hsp40 proteins have human homologs, except for those proteins implicated in fundamental biological processes. Our analysis suggests that P. falciparum has evolved an expanded and specialized Hsp40 protein machinery to enable it successfully to invade and remodel the human erythrocyte, and we propose a model in which these proteins are involved in chaperone-mediated translocation, folding, assembly and regulation of parasite and host proteins. (c) 2007 Published by Elsevier Ltd.