Structural–functional diversity of malaria parasite's PfHSP70-1 and PfHSP40 chaperone pair gives an edge over human orthologs in chaperone-assisted protein folding
Autor: | L Sathish Kumar, Aradhya Tripathi, Ankita Shukla, Chetan Prakash, Sandeep K. Sharma, Ravishankar Ramachandran, Varsha Kumari, Priyabrata Nag, Niti Kumar, Mohammad Anas |
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Rok vydání: | 2020 |
Předmět: |
Protein Folding
Plasmodium falciparum Allosteric regulation Protozoan Proteins HSP72 Heat-Shock Proteins Biochemistry 03 medical and health sciences 0302 clinical medicine Protein structure Humans Molecular Biology 030304 developmental biology 0303 health sciences biology Chemistry Cell Biology HSP40 Heat-Shock Proteins biology.organism_classification Cell biology HSPA1A Proteostasis Chaperone (protein) Proteome biology.protein Protein folding 030217 neurology & neurosurgery |
Zdroj: | Biochemical Journal. 477:3625-3643 |
ISSN: | 1470-8728 0264-6021 |
Popis: | 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. |
Databáze: | OpenAIRE |
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