Exported J domain proteins of the human malaria parasite

Abstract

The heat shock protein 40 (Hsp40) family, also called J domain proteins (JDPs), regulate their Hsp70 partners by ensuring that they are engaging the right substrate at the right time and in the right location within the cell. A number of JDPs can serve as co-chaperone for a particular Hsp70, and so one generally finds many more JDPs than Hsp70s in the cell. In humans there are 13 Hsp70s and 49 JDPs. The human malaria parasite, Plasmodium falciparum, has dedicated an unusually large proportion of its genome to molecular chaperones, with a disproportionately high number of JDPs (PfJDPs) of 49 members. Interestingly, just under half of the PfJDPs are exported into the host cell during the asexual stage of the life cycle, when the malaria parasite invades mature red blood cells. Recent evidence suggests that these PfJDPs may be functionalizing both host and parasite Hsp70s within the infected red blood cell, and thereby driving the renovation of the host cell towards pathological ends. PfJDPs have been found to localize to the host cytosol, mobile structures within the host cytosol (so called “J Dots”), the host plasma membrane, and specialized structures associated with malaria pathology such as the knobs. A number of these exported PfJDPs are essential, and there is growing experimental evidence that they are important for the survival and pathogenesis of the malaria parasite. This review critiques our understanding of the important role these exported PfJDPs play at the host-parasite interface.

Plasmodium falciparum J‐dot localized J domain protein A8iJp modulates the chaperone activity of human HSPA8

“…Parasite protein export through the parasitophorous vacuolar membrane into the host erythrocyte occurs in an unfolded state, necessitating the assistance of chaperones to maintain their translocation competence and aid in folding [11,12]. Only one PfHSP70 chaperone is exported [17], but it is not vital for parasite growth [22], leading researchers to believe that the parasite may utilize the host HSP70 chaperone for protein folding and host erythrocyte remodeling [23]. Since the JDPs can modulate HSP70 protein activity, our lab targets the putative JDPs of P. falciparum that have a propensity to get exported.…”

“…Among the P. falciparum chaperones, only a subset of PfHSP40 (P. falciparum Heat Shock Protein 40) family proteins (18 out of 49) have the PEXEL motif [12][13][14]. Members of the HSP40 family, alternatively referred to as J-domain proteins (JDPs) [15], function as co-chaperones, facilitating the delivery of unfolded polypeptides to the cognate HSP70 proteins for folding and stimulating the ATPase activity [12]. JDPs are categorized into four types based on their canonical regions: J-domain, glycine-rich region, cysteine-rich zinc-binding domain, and C-terminal domain.…”

“…Later, PfHSP70xa PEXEL-negative exported protein, got localized to the J-dots [16,17] and was reported to act as the cognate chaperone for two PfJDPs (PFE0055c and PFA0660w) [18][19][20][21]. Still, the dispensability of PfHSP70x protein [22] for the intraerythrocytic parasite survival made researchers speculate that few of the exported PfJDPs hijack the human erythrocyte HSP70 chaperone function for parasite protein folding [11,23,24]. Recently, a type-IV JDP -PfeCiJp, has been reported as a co-chaperone for the human HsHSPA1 [25].…”

Plasmodium falciparum heat shock proteins as antimalarial drug targets: An update

“… 50 In the parasite, many of the exported PfHSP40s are expressed during the early stages of the asexual phase of the malaria parasite life cycle, and they are vital for malaria protein export and survival during febrile episodes. 51 , 52 , 53 Some of these exported PfHSP40s have been confirmed to functionally interact with the only exported PfHSP70, PfHSP70-x. For example, Daniyan et al 54 and Dutta et al 36 found compelling evidence that the exported type II PfHSP40s, PFA0660w and PFE0055c have a functional association with PfHSP70-x.…”

“…To explore this idea, key differences in the PPIs between P. falciparum and human cochaperone–chaperone complexes have been revealed based on structural analyses. 36 , 53 , 60 , 61 , 62 , 63 Furthermore, molecular docking studies have compared PfHSP70–PfHSP40 complexes to their human HSP70–HSP40 equivalents, and used these complexes to screen drug repurposing small molecule libraries to identify compounds with preferential binding to the malarial over the human system. 64 As expected, the J domain–NBD interfaces of PfHSP70-x–PFE0055c and human HSP70 (HSPA1A)-DNAJA1 both involved multiple topologically equivalent hydrogen bond interactions between highly conserved positively charged J domain helix II residues and NBD negatively charged residues ( Figure 2 ).…”