Affinage · Plasmodium

UIS24

PF3D7_1134000 · heat shock protein 70

Annotated
2026-09-08
43 papers in source corpus 1 papers cited in narrative 1 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PF3D7_1134000 (HSP70-3) is the sole Hsp70 chaperone predicted to localize to the mitochondrion of Plasmodium falciparum (PMID:27253881). Purified PfHsp70-3 is intrinsically prone to self-aggregation, and this aggregation is specifically suppressed by the Hsp70-escort protein PfHep1: co-expression with PfHep1 in E. coli enhances PfHsp70-3 solubility, and purified PfHep1 prevents thermally induced aggregation of PfHsp70-3 but not of unrelated substrates such as malate dehydrogenase or citrate synthase, establishing substrate specificity (PMID:27253881). PfHep1 function depends on zinc, as EDTA chelation abolishes its ability to keep PfHsp70-3 soluble, indicating that a zinc-dependent escort chaperone is required to maintain the folding-competent, non-aggregated state of PfHsp70-3 (PMID:27253881). Beyond this escort relationship, no substrate specificity, ATPase activity, cochaperone network, or in vivo mitochondrial function of PF3D7_1134000 has been characterized in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 1 step
  1. 2016 Medium

    It was unknown how the aggregation-prone, mitochondrially predicted Plasmodium Hsp70 is maintained in a soluble state; this work showed that the escort protein PfHep1 specifically and zinc-dependently prevents PfHsp70-3 self-aggregation, establishing PfHep1 as an obligate cochaperone for PfHsp70-3 solubility.

    Evidence Co-expression solubility assay in E. coli plus in vitro thermal aggregation suppression with purified proteins and EDTA zinc chelation

    PMID:27253881

    Open questions at the time
    • The in vivo mitochondrial localization and physiological function of PfHsp70-3 in the parasite were not tested
    • No client/substrate proteins of PfHsp70-3 or its ATPase/refolding activity were characterized
    • The stoichiometry and structural basis of the PfHsp70-3–PfHep1 interaction were not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether PfHsp70-3 acts as a functional folding chaperone in the parasite mitochondrion, what its substrates and nucleotide-exchange/J-domain cochaperones are, and whether the PfHep1 dependence is essential in vivo remain open.
  • No in vivo genetic or localization data for PF3D7_1134000 in the corpus
  • No identified physiological substrates or partner chaperones beyond PfHep1
  • No structural model of PfHsp70-3 or the escort complex

Mechanism profile

Synthesis pass · controlled-vocabulary classification
Partners
PFHEP1 (HSP70-ESCORT PROTEIN; ZINC-DEPENDENT, SUPPRESSES PFHSP70-3 AGGREGATION) [#0]

Evidence

Reading pass · 1 per-paper finding extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 PfHsp70-3 (PF3D7_1134000), the sole Hsp70 predicted to localize to the P. falciparum mitochondria, undergoes self-aggregation that is specifically suppressed by co-expression with PfHep1 (a Hsp70-escort protein orthologue). Co-expression of PfHsp70-3 with PfHep1 enhanced PfHsp70-3 solubility, and purified PfHep1 suppressed thermally induced aggregation of PfHsp70-3 but not of malate dehydrogenase or citrate synthase, demonstrating substrate specificity. Zinc ions were essential for PfHep1 function, as EDTA chelation abrogated its ability to prevent PfHsp70-3 aggregation. Co-expression in E. coli (solubility assay), in vitro thermal aggregation suppression assay with purified proteins, EDTA chelation to assess zinc dependence PloS one Medium 27253881

Source papers

Stage 0 corpus · 43 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 Demonstration of heat-shock protein 70 in the sporozoite stage of malaria parasites. Parasitology research 182 8153120
1986 A repetitive antigen of Plasmodium falciparum that is homologous to heat shock protein 70 of Drosophila melanogaster. Proceedings of the National Academy of Sciences of the United States of America 159 3095842
1991 Induction and localization of Plasmodium falciparum stress proteins related to the heat shock protein 70 family. Molecular and biochemical parasitology 144 1779989
1989 Homology of the 70-kilodalton antigens from Mycobacterium leprae and Mycobacterium bovis with the Mycobacterium tuberculosis 71-kilodalton antigen and with the conserved heat shock protein 70 of eucaryotes. Infection and immunity 113 2491836
2007 The structural and functional diversity of Hsp70 proteins from Plasmodium falciparum. Protein science : a publication of the Protein Society 103 17766381
2011 Intracellular protozoan parasites of humans: the role of molecular chaperones in development and pathogenesis. Protein and peptide letters 90 20955165
1988 Plasmodium falciparum gene encoding a protein similar to the 78-kDa rat glucose-regulated stress protein. Proceedings of the National Academy of Sciences of the United States of America 80 3045815
2004 Overproduction, purification, and characterization of the Plasmodium falciparum heat shock protein 70. Protein expression and purification 61 14711509
2011 Characterisation of the Plasmodium falciparum Hsp70-Hsp90 organising protein (PfHop). Cell stress & chaperones 59 22005844
2001 Cellular stress and injury responses in the brains of adult Vietnamese patients with fatal Plasmodium falciparum malaria. Neuropathology and applied neurobiology 52 11903925
2005 Plasmodium falciparum heat shock protein 70 is able to suppress the thermosensitivity of an Escherichia coli DnaK mutant strain. Molecular genetics and genomics : MGG 51 15973516
2014 Selective modulation of plasmodial Hsp70s by small molecules with antimalarial activity. Biological chemistry 49 24854538
2010 Plasmodium falciparum encodes a single cytosolic type I Hsp40 that functionally interacts with Hsp70 and is upregulated by heat shock. Cell stress & chaperones 49 21191678
2011 Screening for small molecule modulators of Hsp70 chaperone activity using protein aggregation suppression assays: inhibition of the plasmodial chaperone PfHsp70-1. Biological chemistry 48 21426241
2008 Structure-function study of a Plasmodium falciparum Hsp70 using three dimensional modelling and in vitro analyses. Protein and peptide letters 47 19075824
2011 Gold nanoparticle-based fluorescence immunoassay for malaria antigen detection. Analytical and bioanalytical chemistry 44 22089818
2008 The Plasmodium falciparum heat shock protein 40, Pfj4, associates with heat shock protein 70 and shows similar heat induction and localisation patterns. The international journal of biochemistry & cell biology 43 18674634
2015 Plasmodium falciparum Hop (PfHop) Interacts with the Hsp70 Chaperone in a Nucleotide-Dependent Fashion and Exhibits Ligand Selectivity. PloS one 40 26267894
2017 Polymyxin B inhibits the chaperone activity of Plasmodium falciparum Hsp70. Cell stress & chaperones 39 28455613
2021 Design and synthesis of quinoline-pyrimidine inspired hybrids as potential plasmodial inhibitors. European journal of medicinal chemistry 34 33744688
2019 Comparative structure-function features of Hsp70s of Plasmodium falciparum and human origins. Biophysical reviews 30 31280465
2014 Plasmodial Hsp40 and Hsp70 chaperones: current and future perspectives. Parasitology 29 24666996
2013 Malaria proteomics: insights into the parasite-host interactions in the pathogenic space. Journal of proteomics 27 24140976
1993 Expression of members of the heat-shock protein 70 family in the exoerythrocytic stages of Plasmodium berghei and Plasmodium falciparum. Parasitology research 22 8475027
2013 Expression profiling of Plasmodium berghei HSP70 genes for generation of bright red fluorescent parasites. PloS one 21 24013507
2015 PFB0595w is a Plasmodium falciparum J protein that co-localizes with PfHsp70-1 and can stimulate its in vitro ATP hydrolysis activity. The international journal of biochemistry & cell biology 18 25701168
2017 Extracts Obtained from Pterocarpus angolensis DC and Ziziphus mucronata Exhibit Antiplasmodial Activity and Inhibit Heat Shock Protein 70 (Hsp70) Function. Molecules (Basel, Switzerland) 16 28788073
2014 A secretory multifunctional serine protease, DegP of Plasmodium falciparum, plays an important role in thermo-oxidative stress, parasite growth and development. The FEBS journal 16 24494818
2021 Iso-mukaadial acetate and ursolic acid acetate inhibit the chaperone activity of Plasmodium falciparum heat shock protein 70-1. Cell stress & chaperones 15 34023985
2017 Plasmodium falciparum Heat Shock Protein 70 Lacks Immune Modulatory Activity. Protein and peptide letters 15 28201964
1996 Further characterization of a 58 kDa Plasmodium berghei phosphoprotein as a cochaperone. Molecular and biochemical parasitology 15 9010839
2023 The Plasmodium falciparum exported J domain proteins fine-tune human and malarial Hsp70s: pathological exploitation of proteostasis machinery. Frontiers in molecular biosciences 11 37457831
2016 Plasmodium falciparum Hep1 Is Required to Prevent the Self Aggregation of PfHsp70-3. PloS one 9 27253881
2024 A promising class of antiprotozoal agents, design and synthesis of novel Pyrimidine-Cinnamoyl hybrids. European journal of medicinal chemistry 5 39549508
2024 Phytochemical evaluation of Ziziphus mucronata and Xysmalobium undulutum towards the discovery and development of anti-malarial drugs. Malaria journal 4 38734650
2009 The effect of mimicking febrile temperature and drug stress on malarial development. Annals of clinical microbiology and antimicrobials 3 19523215
2024 Understanding the complex formation of falstatin; an endogenous macromolecular inhibitor of falcipains. International journal of biological macromolecules 2 38460641
1994 Serine-stretch protein (SERP) of Plasmodium falciparum corresponds to the exoantigen Ag2, a target of antibodies associated with protection against malaria. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 1 8167001
2026 Flow cytometry-based evaluation of hepatic infection by non-fluorescent Plasmodium parasites. International journal for parasitology 0 41864451
2026 Development of domain-specific probes of Plasmodium falciparum heat shock protein 70-1. Antimicrobial agents and chemotherapy 0 42390429
2025 Acanthospermum australe Extract Inhibits the Chaperone Activity of Plasmodium falciparum Heat Shock Protein 70-1. Microorganisms 0 41011525
2024 Iso-mukaadial acetate and ursolic acid acetate bind to Plasmodium Falciparum heat shock protein 70: towards targeting parasite protein folding pathway. BMC chemistry 0 38500145
1999 [Finding of new FCC1/HN antigenic expressed sequence tag(ESTs) of Plasmodium falciparum]. Zhongguo ji sheng chong xue yu ji sheng chong bing za zhi = Chinese journal of parasitology & parasitic diseases 0 12563736