Plasmodial HSP70s are functionally adapted to the malaria parasite life cycle

Przyborski, Jude M.; Diehl, Mathias; Blatch, Gregory L.

doi:10.3389/fmolb.2015.00034

Cited by 40 publications

(27 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been proposed that nearly 10% of P. falciparum’s proteome is characterized by prion-like repeats and that at least 30% of the proteome is characterized by glutamate/asparagine rich segments [ 21 , 22 ]. For this reason, it is thought that P. falciparum Hsp70s are adapted to fold and stabilize its mis-folding-prone proteome [ 23 , 24 , 25 ]. To this end, we previously demonstrated that a P. falciparum chaperone, PfHsp70-x, which is exported to the parasite-infected red blood cell [ 26 ], exhibits preference for asparagine rich peptides, further suggesting that P. falciparum Hsp70s are primed to bind mis-folded proteins of the parasite [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

Comparative Characterization of Plasmodium falciparum Hsp70-1 Relative to E. coli DnaK Reveals the Functional Specificity of the Parasite Chaperone

et al. 2020

View full text Add to dashboard Cite

Hsp70 is a conserved molecular chaperone. How Hsp70 exhibits specialized functions across species remains to be understood. Plasmodium falciparum Hsp70-1 (PfHsp70-1) and Escherichia coli DnaK are cytosol localized molecular chaperones that are important for the survival of these two organisms. In the current study, we investigated comparative structure-function features of PfHsp70-1 relative to DnaK and a chimeric protein, KPf, constituted by the ATPase domain of DnaK and the substrate binding domain (SBD) of PfHsp70-1. Recombinant forms of the three Hsp70s exhibited similar secondary and tertiary structural folds. However, compared to DnaK, both KPf and PfHsp70-1 were more stable to heat stress and exhibited higher basal ATPase activity. In addition, PfHsp70-1 preferentially bound to asparagine rich peptide substrates, as opposed to DnaK. Recombinant P. falciparum adenosylmethionine decarboxylase (PfAdoMetDC) co-expressed in E. coli with either KPf or PfHsp70-1 was produced as a fully folded product. Co-expression of PfAdoMetDC with heterologous DnaK in E. coli did not promote folding of the former. However, a combination of supplementary GroEL plus DnaK improved folding of PfAdoMetDC. These findings demonstrated that the SBD of PfHsp70-1 regulates several functional features of the protein and that this molecular chaperone is tailored to facilitate folding of plasmodial proteins.

show abstract

Section: Introductionmentioning

confidence: 99%

Comparative Characterization of Plasmodium falciparum Hsp70-1 Relative to E. coli DnaK Reveals the Functional Specificity of the Parasite Chaperone

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Bioinformatic analysis found a correlation between the over-representation of homorepeat containing proteins and the abundance of proteins with putative PrLDs, which were proposed to account for as much as 25% of the parasite proteome ( Singh et al, 2004 ). The biological significance of these protein domains is not clear ( Muralidharan and Goldberg, 2013 ), but P. falciparum has evolved a very efficient proteostatic system to cope with such an aggregation-prone proteome ( Muralidharan et al, 2012 ; Muralidharan and Goldberg, 2013 ; Przyborski et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Discovering Putative Prion-Like Proteins in Plasmodium falciparum: A Computational and Experimental Analysis

et al. 2018

View full text Add to dashboard Cite

Prions are a singular subset of proteins able to switch between a soluble conformation and a self-perpetuating amyloid state. Traditionally associated with neurodegenerative diseases, increasing evidence indicates that organisms exploit prion-like mechanisms for beneficial purposes. The ability to transit between conformations is encoded in the so-called prion domains, long disordered regions usually enriched in glutamine/asparagine residues. Interestingly, Plasmodium falciparum, the parasite that causes the most virulent form of malaria, is exceptionally rich in proteins bearing long Q/N-rich sequence stretches, accounting for roughly 30% of the proteome. This biased composition suggests that these protein regions might correspond to prion-like domains (PrLDs) and potentially form amyloid assemblies. To investigate this possibility, we performed a stringent computational survey for Q/N-rich PrLDs on P. falciparum. Our data indicate that ∼10% of P. falciparum protein sequences have prionic signatures, and that this subproteome is enriched in regulatory proteins, such as transcription factors and RNA-binding proteins. Furthermore, we experimentally demonstrate for several of the identified PrLDs that, despite their disordered nature, they contain inner short sequences able to spontaneously self-assemble into amyloid-like structures. Although the ability of these sequences to nucleate the conformational conversion of the respective full-length proteins should still be demonstrated, our analysis suggests that, as previously described for other organisms, prion-like proteins might also play a functional role in P. falciparum.

show abstract

“…This process is essential for the development of the parasite and is associated with the pathology of the infection [ 9 , 10 ]. Among the exported proteins are heat shock proteins, functioning as molecular chaperones that are proposed to be highly adapted to the malaria parasite lifecycle [ 11 ]. The heat shock protein 70 (Hsp70) chaperone and its co-chaperone heat shock protein 40 (Hsp40) are involved in facilitating protein folding, stabilization, degradation, and translocation across membranes [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

The Malarial Exported PFA0660w Is an Hsp40 Co-Chaperone of PfHsp70-x

et al. 2016

Self Cite

View full text Add to dashboard Cite

Plasmodium falciparum, the human pathogen responsible for the most dangerous malaria infection, survives and develops in mature erythrocytes through the export of proteins needed for remodelling of the host cell. Molecular chaperones of the heat shock protein (Hsp) family are prominent members of the exportome, including a number of Hsp40s and a Hsp70. PFA0660w, a type II Hsp40, has been shown to be exported and possibly form a complex with PfHsp70-x in the infected erythrocyte cytosol. However, the chaperone properties of PFA0660w and its interaction with human and parasite Hsp70s are yet to be investigated. Recombinant PFA0660w was found to exist as a monomer in solution, and was able to significantly stimulate the ATPase activity of PfHsp70-x but not that of a second plasmodial Hsp70 (PfHsp70-1) or a human Hsp70 (HSPA1A), indicating a potential specific functional partnership with PfHsp70-x. Protein binding studies in the presence and absence of ATP suggested that the interaction of PFA0660w with PfHsp70-x most likely represented a co-chaperone/chaperone interaction. Also, PFA0660w alone produced a concentration-dependent suppression of rhodanese aggregation, demonstrating its chaperone properties. Overall, we have provided the first biochemical evidence for the possible role of PFA0660w as a chaperone and as co-chaperone of PfHsp70-x. We propose that these chaperones boost the chaperone power of the infected erythrocyte, enabling successful protein trafficking and folding, and thereby making a fundamental contribution to the pathology of malaria.

show abstract

Plasmodial HSP70s are functionally adapted to the malaria parasite life cycle

Cited by 40 publications

References 56 publications

Comparative Characterization of Plasmodium falciparum Hsp70-1 Relative to E. coli DnaK Reveals the Functional Specificity of the Parasite Chaperone

Comparative Characterization of Plasmodium falciparum Hsp70-1 Relative to E. coli DnaK Reveals the Functional Specificity of the Parasite Chaperone

Discovering Putative Prion-Like Proteins in Plasmodium falciparum: A Computational and Experimental Analysis

The Malarial Exported PFA0660w Is an Hsp40 Co-Chaperone of PfHsp70-x

Contact Info

Product

Resources

About