Chaperonin activity of Plasmodium prefoldin complex is essential to guard proteotoxic stress response and presents a new target for drug discovery
Shoaib, R.; Kumar, V.; Garg, S.; Saini, M.; Kumari, J.; Maurya, P.; Gupta, A.; Gupta, N.; Singh, H.; Verma, P.; Jain, R.; Biswas, S.; Behl, A.; Abid, M.; Singh, S.
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The intraerythrocytic growth of malaria parasite is challenged by the presence of proteotoxic stress and intrinsically unstructured proteins in the cytoplasm due to formation of toxic heme during haemoglobin digestion. To overcome the unavoidable stress and maintain the cellular protein homeostasis, parasite encodes for a number of chaperones and co-chaperones. Here, we functionally characterize the Plasmodium falciparum prefoldins (PfPFD1-6), a hexameric co-chaperone complex, for their role in protein homeostasis. We demonstrate that PfPFD1-6 localise to cytosol of the parasite and the subunits perform an orchestrated interaction (-PFD3-PFD2-PFD1-PFD5-PFD6-PFD4-) to form an active jelly-fish like complex. Biperiden, an N-propylpiperidine analogue identified by chemotype search from FDA, strongly binds and restricts the formation of prefoldin complex and inhibited its interaction with the substrates, PfMSP-1 and -tubulin-I. Biperiden treatment potently inhibited the in vitro (IC50: 1M) and in vivo growth of malaria parasite. Thus, this study provides novel virtues towards understanding the role of PfPFDs in regulating protein homeostasis and opens new avenues for drug discovery against malaria.
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