Abstract
Plasmodium falciparum has the most adenine (A)- and thymine (T)-rich genome known to date, and 24–30% of the P. falciparum proteome contains asparagine (N) and glutamine (Q) residues. In general, asparagine repeats in proteins increase the propensity for aggregation, especially at elevated temperatures, which occur routinely in P. falciparum parasites during exoerythrocytic and erythrocytic developmental stages in a vertebrate host. The P. falciparum exported chaperone machinery is comprised of an exported PfHsp70-x protein and its co-chaperone PfHsp40-x1 in the host erythrocyte compartment, and PfHsp70-z and its co-chaperones in the parasite cytoplasm have been identified. In vitro assays reveal that these chaperone partners function in refolding of asparagine-rich polypeptides. The identification and chaperoning of exported poly-asparagine-containing proteins, and the biological roles and the protection mechanisms of P. falciparum during febrile conditions by the exported chaperone machinery are discussed.
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References
Acharya P, Kumar R, Tatu U (2007) Chaperoning a cellular upheaval in malaria: heat shock proteins in Plasmodium falciparum. Mol Biochem Parasitol 153(2):85–94
Alkhalil A, Cohn JV, Wagner MA, Cabrera JS, Rajapandi T, Desai SA (2004) Plasmodium falciparum likely encodes the principal anion channel on infected human erythrocytes. Blood 104(13):4279–4286 (Epub 2004 Aug 19)
Behl A, Kumar V, Bisht A et al (2019) Cholesterol bound Plasmodium falciparum co-chaperone ‘PFA0660w’ complexes with major virulence factor ‘PfEMP1’ via chaperone ‘PfHsp70-x’. Sci Rep 9:2664
Botha M, Pesce ER, Blatch GL (2007) The Hsp40 proteins of Plasmodium falciparum and other apicomplexa: regulating chaperone power in the parasite and the host. Int J Biochem Cell Biol 39(10):1781–1803
Chakafana G, Zininga T, Shonhai A (2019) Comparative structure-function features of Hsp70s of Plasmodium falciparum and human origins. Biophys Rev 11:591–602. https://doi.org/10.1007/s12551-019-00563-w
Cohn JV, Alkhalil A, Wagner MA, Rajapandi T, Desai SA (2003) Extracellular lysines on the plasmodial surface anion channel involved in Na + exclusion. Mol Biochem Parasitol 132(1):27–34
Day J, Passecker A, Beck HP, Vakonakis I (2019) The Plasmodium falciparum Hsp70-x chaperone assists the heat stress response of the malaria parasite. FASEB J 33(12):14611–14624. https://doi.org/10.1096/fj.201901741R
Dragovic Z, Broadley SA, Shomura Y, Bracher A, Hartl FU (2006) Molecular chaperones of the Hsp110 family act as nucleotide exchange factors of Hsp70s. EMBO J 25(11):2519–2528. https://doi.org/10.1038/sj.emboj.7601138
Eisenberg E, Greene LE (2007) Multiple roles of auxilin and hsc70 in clathrin-mediated endocytosis. Traffic 8(6):640–646 (Epub 2007 May 4)
Foley M, Tilley L (1998) Protein trafficking in malaria-infected erythrocytes. Int J Parasitol 11:1671–1680
Gardner MJ, Hall N, Fung E, White O, Berriman M et al (2002) Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419:498–511
Gormley JA, Howard RJ, Taraschi TF (1992) Trafficking of malarial proteins to the host cell cytoplasm and erythrocyte surface membrane involves multiple pathways. J Cell Biol 119(6):1481–1495
Halfmann R, Alberti S, Krishnan R, Lyle N, O’Donnell CW et al (2011) Opposing effects of glutamine and asparagine govern prion formation by intrinsically disordered proteins. Mol Cell 43:72–84
Hiller NL, Bhattacharjee S, van Ooij C, Liolios K, Harrison T, Lopez- Estraño C, Haldar K (2004) A host-targeting signal in virulence proteins reveals a secretome in malarial infection. Science 306(5703):1897–1898
Kriek N, Tilley L, Horrocks P, Pinches R, Elford BC, Ferguson DJ, Lingelbach K, Newbold CI (2003) Characterization of the pathway for transport of the cytoadherence-mediating protein, PfEMP1, to the host cell surface in malaria parasite-infected erythrocytes. Mol Microbiol 50(4):1215–1227
Külzer S, Rug M, Brinkmann K, Cannon P, Cowman A, Lingelbach K, Blatch GL, Maier AG, Przyborski JM (2010) Parasite-encoded Hsp40 proteins define novel mobile structures in the cytosol of the P. falciparum-infected erythrocyte. Cell Microbiol 12:1398–1420 [PubMed: 20482550]
Külzer S, Charnaud S, Dagan T, Riedel J, Mandal P, Pesce ER, Blatch GL, Crabb BS, Gilson PR, Przyborski JM (2012) Plasmodium falciparum-encoded exported hsp70/hsp40 chaperone/co-chaperone complexes within the host erythrocyte. Cell Microbiol 14:1784–1795 [PubMed: 22925632]
Lopez N, Aron R, Craig EA (2003) Specificity of class II Hsp40 Sis1 in maintenance of yeast prion [RNQ +]. Mol Biol Cell 14(3):1172–1181
Mabate B, Zininga T, Ramatsui L et al (2018) Structural and biochemical characterization of Plasmodium falciparum Hsp70-x reveals functional versatility of its C-terminal EEVN motif. Proteins 86:1189–1201. https://doi.org/10.1002/prot.25600
Marti M, Good RT, Rug M, Knuepfer E, Cowman AF (2004) Targeting malaria virulence and remodeling proteins to the host erythrocyte. Science 306:1930–1933
Marti M, Baum J, Rug M, Tilley L, Cowman AF (2005) Signal-mediated export of proteins from the malaria parasite to the host erythrocyte. J Cell Biol 171:587–592
Michelitsch MD, Weissman JS (2000) A census of glutamine/asparagine-rich regions: implications for their conserved function and the prediction of novel prions. Proc Natl Acad Sci USA 97(22):11910–11915
Muralidharan V, Goldberg DE (2013) Asparagine repeats in Plasmodium falciparum proteins: good for nothing? PLoS Pathog 9(8):e1003488. https://doi.org/10.1371/journal.ppat.1003488
Muralidharan V, Oksman A, Pal P, Lindquist S, Goldberg DE (2012) Plasmodium falciparum heat shock protein 110 stabilizes the asparagine repeat-rich parasite proteome during malarial fevers. Nat Commun 3:1310
Oakley MS, Kumar S, Anantharaman V, Zheng H, Mahajan B, Haynes JD, Moch JK, Fairhurst R, McCutchan TF, Aravind L (2007) Molecular factors and biochemical pathways induced by febrile temperature in intraerythrocytic Plasmodium falciparum parasites. Infect Immun 75(4):2012–2025
Pallarès I, de Groot NS, Iglesias V, Sant’Anna R, Biosca A, Fernàndez-Busquets X, Ventura S (2018) Discovering putative prion-like proteins in Plasmodium falciparum: a computational and experimental analysis. Front Microbiol 9:1737. https://doi.org/10.3389/fmicb.2018.01737
Papakrivos J, Newbold CI, Lingelbach K (2005) A potential novel mechanism for the insertion of a membrane protein revealed by a biochemical analysis of the Plasmodium falciparum cytoadherence molecule PfEMP-1. Mol Microbiol 55:1272–1284
Przyborski JM, Diehl M, Blatch GL (2015) Plasmodial HSP70s are functionally adapted to the malaria parasite life cycle. Front Mol Biosci 2:34. https://doi.org/10.3389/fmolb.2015.00034
Rajapandi T, Wu C, Eisenberg E, Greene L (1998) Characterization of D10S and K71E mutants of human cytosolic hsp70. Biochemistry 19(37(20)):7244–7250
Rajapandi T, Greene LE, Eisenberg E (2000) The molecular chaperones Hsp90 and Hsc70 are both necessary and sufficient to activate hormone binding by glucocorticoid receptor. J Biol Chem 275(29):22597–22604
Sargeant TJ, Marti M, Caler E, Carlton JM, Simpson K, Speed TP, Cowman AF (2006) Lineage-specific expansion of proteins exported to erythrocytes in malaria parasites. Genome Biol 7(2):R12
Schatz G, Dobberstein B (1996) Common principles of protein translocation across membranes. Science 271(5255):1519–1526
Singh GP, Chandra BR, Bhattacharya A, Akhouri RR, Singh SK, Sharma A (2004) Hyper-expansion of asparagines correlates with an abundance of proteins with prion-like domains in Plasmodium falciparum. Mol Biochem Parasitol 137(2):307–319
Sondheimer N, Lopez N, Craig EA, Lindquist S (2001) The role of Sis1 in the maintenance of the [RNQ +] prion. EMBO J 20(10):2435–2442
Spielmann T, Hawthorne PL, Dixon MW, Hannemann M, Klotz K, Kemp DJ, Klonis N, Tilley L, Trenholme KR, Gardiner DL (2006) A cluster of ring stage-specific genes linked to a locus implicated in cytoadherence in Plasmodium falciparum codes for PEXEL-negative and PEXEL-positive proteins exported into the host cell. Mol Biol Cell 17(8):3613–3624
Taraschi TF, Trelka D, Martinez S, Schneider T, O’Donnell ME (2001) Vesicle-mediated trafficking of parasite proteins to the host cell cytosol and erythrocyte surface membrane in Plasmodium falciparum infected erythrocytes. Int J Parasitol 12:1381–1391
van Ooij C, Haldar K (2007) Protein export from Plasmodium parasites. Cell Microbiol 9(3):573–582 (Epub 2007 Jan 11)
Zininga T, Achilonu I, Hoppe H, Prinsloo E, Dirr HW, Shonhai A (2016) Plasmodium falciparum Hsp70-z, an Hsp110 homologue, exhibits independent chaperone activity and interacts with Hsp70-1 in a nucleotide-dependent fashion. Cell Stress Chaperones 21(3):499–513. https://doi.org/10.1007/s12192-016-0678-4
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The author would like to thank Paul Gass, Coppin State University for critical reading of the manuscript and helpful suggestions.
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TR conceived and devised the study, collected data and analyzed results, made interpretations, collected references, wrote the manuscript.
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Rajapandi, T. Chaperoning of asparagine repeat-containing proteins in Plasmodium falciparum. J Parasit Dis 44, 687–693 (2020). https://doi.org/10.1007/s12639-020-01251-3
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DOI: https://doi.org/10.1007/s12639-020-01251-3