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Structural-functional diversity of malaria parasite's PfHSP70-1 and PfHSP40 chaperone pair gives an edge over human orthologs in chaperone-assisted protein folding.

Authors
  • Anas, Mohammad1
  • Shukla, Ankita2
  • Tripathi, Aradhya1
  • Kumari, Varsha1
  • Prakash, Chetan1
  • Nag, Priyabrata1
  • Kumar, L Sathish1
  • Sharma, Sandeep K3, 4
  • Ramachandran, Ravishankar2, 4
  • Kumar, Niti1, 4
  • 1 Department of Molecular Parasitology and Immunology, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, Uttar Pradesh, India. , (India)
  • 2 Department of Molecular and Structural Biology, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, Uttar Pradesh, India. , (India)
  • 3 Department of Food, Drug and Chemical Toxicology, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow 226001, Uttar Pradesh, India. , (India)
  • 4 Academy of Scientific and Innovative Research (AcSIR), Delhi, India. , (India)
Type
Published Article
Journal
Biochemical Journal
Publisher
Portland Press
Publication Date
Sep 30, 2020
Volume
477
Issue
18
Pages
3625–3643
Identifiers
DOI: 10.1042/BCJ20200434
PMID: 32893851
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Plasmodium falciparum, the human malaria parasite harbors a metastable proteome which is vulnerable to proteotoxic stress conditions encountered during its lifecycle. How parasite's chaperone machinery is able to maintain its aggregation-prone proteome in functional state, is poorly understood. As HSP70-40 system forms the central hub in cellular proteostasis, we investigated the protein folding capacity of PfHSP70-1 and PfHSP40 chaperone pair and compared it with human orthologs (HSPA1A and DNAJA1). Despite the structural similarity, we observed that parasite chaperones and their human orthologs exhibit striking differences in conformational dynamics. Comprehensive biochemical investigations revealed that PfHSP70-1 and PfHSP40 chaperone pair has better protein folding, aggregation inhibition, oligomer remodeling and disaggregase activities than their human orthologs. Chaperone-swapping experiments suggest that PfHSP40 can also efficiently cooperate with human HSP70 to facilitate the folding of client-substrate. SPR-derived kinetic parameters reveal that PfHSP40 has higher binding affinity towards unfolded substrate than DNAJA1. Interestingly, the observed slow dissociation rate of PfHSP40-substrate interaction allows PfHSP40 to maintain the substrate in folding-competent state to minimize its misfolding. Structural investigation through small angle x-ray scattering gave insights into the conformational architecture of PfHSP70-1 (monomer), PfHSP40 (dimer) and their complex. Overall, our data suggest that the parasite has evolved functionally diverged and efficient chaperone machinery which allows the human malaria parasite to survive in hostile conditions. The distinct allosteric landscapes and interaction kinetics of plasmodial chaperones open avenues for the exploration of small-molecule based antimalarial interventions. © 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

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