Prefoldin subunit 6 of Plasmodium falciparum binds merozoite surface protein‐1

Abstract

Malaria is a human disease caused by eukaryotic protozoan parasites of the Plasmodium genus. Plasmodium falciparum (Pf) causes the most lethal form of human malaria and is responsible for widespread mortality worldwide. Prefoldin is a hetero-hexameric molecular complex that binds and delivers unfolded proteins to chaperonin for correct folding. The prefoldin PFD6 is predicted to interact with merozoite surface protein-1 (MSP-1), a protein well known to play a pivotal role in erythrocyte binding and invasion by Plasmodium merozoites. We previously found that the Plasmodium falciparum (Pf) genome contains six prefoldin genes and a prefoldin-like gene whose molecular functions are unidentified. Here, we analysed the expression of PfPFD-6 during the asexual blood stages of the parasite and investigated its interacting partners. PfPFD-6 was found to be significantly expressed at the trophozoite and schizont stages. Pull down assays suggest PfPFD-6 interacts with MSP-1. In silico analysis suggested critical residues involved in the PfPFD-6-MSP-1 interaction. Our data suggest PfPFD-6 may play a role in stabilizing or trafficking MSP-1.

Prefoldin Function in Cellular Protein Homeostasis and Human Diseases

“…Merozoite surface protein-1 (MSP-1) of Pf plays an essential role in the binding of merozoites to human erythrocytes and infecting erythrocytes. Pf PFD6 was shown to interact with MSP-1 suggesting that Pf PFD6 might stabilize and assist the trafficking of MSP-1, which indirectly promotes erythrocyte invasion and pathogenicity of malaria ( Kumar et al, 2020 ).…”

Chaperonin activity of Plasmodium prefoldin complex is essential to guard proteotoxic stress response and presents a new target for drug discovery

“…Plasmodium falciparum 3D7 (Pf 3D7) PFD subunits, namely Pf PFD1 (20 kDa), Pf PFD2 (19 kDa), Pf PFD3 (24 kDa), Pf PFD4 (17 kDa), Pf PFD5 (30 kDa) and Pf PFD6 (16 kDa), were cloned in pET-28a (+) and over-expressed in E. coli strain BL21-DE3. Recombinant 6x-His- Pf PFD (r Pf PFD) subunits were purified using Ni-NTA resin, as described previously (Kumar et al, 2022a) (Fig. S1).…”

“…We previously reported that MSP-1 is a substrate of Pf PFD6 (Kumar et al, 2022a). MSP-1 is a critical molecule in the parasite egress and invasion of fresh RBCs.…”

Putative prefoldin complex subunit 5 of Plasmodium berghei is crucial for microtubule formation and parasite development in the mosquito

“…The fact that the P. berghei blood stage appears not to be substantially affected by the loss of Pb PCS5 implies marked differences in nuclei distribution and microtubule organization in mosquito and blood stages or some redundancy in the prefoldin complex organization only in blood stage development. In fact, subunit 6 of prefoldin was already described to bind to merozoite surface protein 1 (MSP1) during P. falciparum blood stage development (Kumar et al., 2020). MSP1 is a major surface protein of merozoites and is explored as a vaccine (Blank et al., 2020).…”

“…Among them, the putative prefoldin complex subunit 5 ( Pb PCS5, PBANKA_0920100) gene, encoding for the Pb PCPS5 protein showed a drastic block in liver stage development (log 2 ‐fold reduction = −7.404), which correlates with an increased expression level of Pb PCS5 mRNA during parasite liver stage development observed by RNA seq analysis (Table 1) (Caldelari et al., 2019; Otto et al., 2014). A recent study showed that subunit 6 of the prefoldin complex of P. falciparum interacts with merozoite surface protein 1 ( Pf MSP1) during the late stages of asexual blood development (Kumar et al., 2020). Prefoldin is a heterohexameric chaperone complex known to be involved in the assembly and maintenance of actin as well as α‐ and β‐tubulins in a wide range of eukaryotes such as yeast, C. elegans and Arabidopsis (Gao et al., 1992; Lundin et al., 2008; Martín‐Benito et al., 2002; Rodríguez‐Milla & Salinas, 2009; Yaffe et al., 1992).…”