Plasmodium falciparum Hsp70-z, an Hsp110 homologue, exhibits independent chaperone activity and interacts with Hsp70-1 in a nucleotide-dependent fashion.

Tawanda Zininga,Earl Prinsloo,Addmore Shonhai,Ikechukwu Achilonu,Heinrich Hoppe,Heini W Dirr

doi:10.1007/s12192-016-0678-4

Abstract

The role of molecular chaperones, among them heat shock proteins (Hsps), in the development of malaria parasites has been well documented. Hsp70s are molecular chaperones that facilitate protein folding. Hsp70 proteins are composed of an N-terminal nucleotide binding domain (NBD), which confers them with ATPase activity and a C-terminal substrate binding domain (SBD). In the ADP-bound state, Hsp70 possesses high affinity for substrate and releases the folded substrate when it is bound to ATP. The two domains are connected by a conserved linker segment. Hsp110 proteins possess an extended lid segment, a feature that distinguishes them from canonical Hsp70s. Plasmodium falciparum Hsp70-z (PfHsp70-z) is a member of the Hsp110 family of Hsp70-like proteins. PfHsp70-z is essential for survival of malaria parasites and is thought to play an important role as a molecular chaperone and nucleotide exchange factor of its cytosolic canonical Hsp70 counterpart, PfHsp70-1. Unlike PfHsp70-1 whose functions are fairly well established, the structure-function features of PfHsp70-z remain to be fully elucidated. In the current study, we established that PfHsp70-z possesses independent chaperone activity. In fact, PfHsp70-z appears to be marginally more effective in suppressing protein aggregation than its cytosol-localized partner, PfHsp70-1. Furthermore, based on coimmunoaffinity chromatography and surface plasmon resonance analyses, PfHsp70-z associated with PfHsp70-1 in a nucleotide-dependent fashion. Our findings suggest that besides serving as a molecular chaperone, PfHsp70-z could facilitate the nucleotide exchange function of PfHsp70-1. These dual functions explain why it is essential for parasite survival.

Highlights

Heat shock proteins (Hsps) play an important role in the development of the main agent of malaria, Plasmodium falciparum
Hsp110 residues that are known to be important for the interaction with Hsp70 (Schuermann et al 2008) are more highly conserved in the Hsp110NBD compared to those in the Hsp110SBD
PfHsp70-z is an essential molecule which localizes to the parasite cytosol and is thought to inhibit aggregation of malarial asparagine repeat-rich proteins (Muralidharan et al 2012)

Summary

Introduction

Heat shock proteins (Hsps) play an important role in the development of the main agent of malaria, Plasmodium falciparum. Two occur in the cytosol: PfHsp70-z/PfHsp110c and PfHsp701 (Shonhai et al 2007; Muralidharan et al 2012). PfHsp is a well-characterized canonical Hsp involved in prevention of protein aggregation and facilitates protein folding (Shonhai et al 2008). PfHsp70-z was previously shown to be an essential protein implicated in the folding of proteins possessing asparagine-rich repeats (Muralidharan et al 2012). We previously demonstrated that the protein is heat-induced and fairly stable against heat stress, suggesting that it plays an important role in the cytoprotection of malaria parasites against hostile conditions prevailing in the human host (Zininga et al 2015a). Apart from its proposed function as a chaperone based on studies in P. falciparum parasites, evidence for the direct function of this protein in protein quality control remains to be demonstrated

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