title: The Hsp40 proteins of Plasmodium falciparum and other apicomplexa: regulating chaperone power in the parasite and the host.
abstract: Extensive structural and functional remodelling of Plasmodium 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 40kDa (Hsp40) family, and six members of the heat shock protein 70kDa (Hsp70) family. Nearly half of the Hsp40 proteins of P. falciparum 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. falciparum Hsp40 chaperone machinery. In addition to the types I, II and III Hsp40 proteins all exhibiting the signature J-domain, the P. falciparum genome also encodes a number of specialized Hsp40 proteins with a J-like domain, which we have categorized as type IV Hsp40 proteins. Analysis of the potential P. falciparum 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. falciparum to those of other apicomplexa reveals that most of the proteins (especially the PEXEL/HT-containing proteins) are unique to P. falciparum. Furthermore, very few of the P. falciparum 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.
authors.affiliation: Department of Biochemistry, Microbiology and Biotechnology, Rhodes University, Grahamstown 6140, South Africa.
authors.forename: M
authors.initials: M
authors.lastname: Botha
authors.forename: E-R
authors.initials: ER
authors.lastname: Pesce
authors.forename: G L
authors.initials: GL
authors.lastname: Blatch
mesh_terms: D000818:Animals; D016782:Apicomplexa / Q000235:genetics / Q000502:physiology*; D017124:Conserved Sequence; D004912:Erythrocytes / Q000378:metabolism; D019143:Evolution, Molecular; D050956:HSP40 Heat-Shock Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006790:Host-Parasite Interactions / Q000235:genetics*; D006801:Humans; D008954:Models, Biological; D018832:Molecular Chaperones / Q000502:physiology*; D010802:Phylogeny; D010963:Plasmodium falciparum / Q000235:genetics / Q000502:physiology*; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid
chemical_list: D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D018832:Molecular Chaperones