Affinage · Plasmodium

ERC

PF3D7_1108600 · endoplasmic reticulum-resident calcium binding protein

Annotated
2026-09-08
10 papers in source corpus 5 papers cited in narrative 5 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ERC (PF3D7_1108600) is an endoplasmic reticulum-resident calcium-binding protein of P. falciparum that functions as an essential early regulator of the parasite egress proteolytic cascade (PMID:9364972, PMID:32098818). It carries six EF-hand calcium-binding domains and a C-terminal IDEL ER-retention motif; its calcium-binding activity was confirmed directly and its ER residence established by co-localization with the ER marker Pfgrp, with expression rising as parasites mature (PMID:9364972). Conditional knockdown showed ERC is required for asexual blood-stage growth and specifically for rupture of the parasitophorous vacuole membrane during egress; mechanistically, ERC is required for proteolytic maturation of the aspartic protease plasmepsin X, which in turn enables maturation of the subtilisin-like protease SUB1 and processing of downstream cascade substrates, while ERC loss does not affect protein trafficking or calcium storage (PMID:32098818). Beyond its role upstream of this proteolytic cascade, ERC has been reported to associate with the ER-resident serpentine receptor SR10 (PMID:32890576), but the functional consequence of this interaction for ERC has not been characterized in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 1997 High

    Established that PF3D7_1108600 is a genuine ER-resident calcium-binding protein, defining its subcellular niche and biochemical activity before any functional role was known.

    Evidence 45Ca2+-blotting, confocal co-localization with ER marker Pfgrp, and partial protein/gene sequencing in P. falciparum asexual stages

    PMID:9364972

    Open questions at the time
    • No cellular or growth phenotype tested at this stage
    • Functional purpose of calcium binding not addressed
    • Interaction partners unidentified
  2. 2012 Medium

    Linked ERC to endoperoxide antimalarial action by identifying it as a high-affinity binder of an endoperoxide probe, raising the possibility it is a drug-relevant target.

    Evidence Chemical proteomics affinity pulldown with endoperoxide probe N-346 and proteomic expression profiling after N-89/N-251 treatment in P. falciparum

    PMID:23061985

    Open questions at the time
    • Single pulldown without reciprocal validation or mutagenesis
    • Direct binding site not mapped
    • Whether the interaction is causal for drug action untested
  3. 2020 High

    Defined the essential function of ERC by placing it upstream of the egress proteolytic cascade, answering what this ER calcium-binding protein actually does for the parasite.

    Evidence Conditional knockdown, double-mutant epistasis, immunoblot of PMX and SUB1 maturation, and PVM rupture assay in P. falciparum

    PMID:32098818

    Open questions at the time
    • Molecular mechanism by which ERC promotes PMX maturation unresolved
    • Whether ERC calcium binding is required for the egress function untested
    • Direct physical link between ERC and PMX not demonstrated
  4. 2020 Medium

    Identified a physical partner for ERC, the ER-resident serpentine receptor SR10, hinting at a protein-interaction context within the ER.

    Evidence Co-immunoprecipitation and co-localization assays in P. falciparum

    PMID:32890576

    Open questions at the time
    • Single Co-IP without reciprocal pull-down
    • Functional consequence of the interaction for ERC not mapped
    • Relationship of SR10 binding to the egress role unknown
  5. 2024 Low

    Extended the egress-cascade model to a rodent malaria system by showing endoperoxide treatment coordinately suppresses PbERC and downstream egress-gene transcripts.

    Evidence qRT-PCR of PbERC, plasmepsin X, SUB1, and MSP1 after transdermal N-89 treatment in P. berghei-infected mice

    PMID:39740755

    Open questions at the time
    • Expression measurement only; no protein-level or mechanistic assay on ERC function
    • Cannot distinguish direct effect on ERC from general drug-induced stress
    • Ortholog function not independently validated by genetics in P. berghei

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular mechanism by which an ER calcium-binding protein controls proteolytic maturation of plasmepsin X, and the role of its calcium binding and SR10 interaction in that process, remains unresolved.
  • No structural or biochemical account of how ERC enables PMX maturation
  • Contribution of the six EF-hands / calcium binding to egress function untested
  • Whether SR10 association participates in the egress pathway unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification
Partners
PLASMEPSIN X (PMX; ERC REQUIRED FOR ITS PROTEOLYTIC MATURATION) [#1]SR10 (ER-RESIDENT SERPENTINE RECEPTOR; CO-IP AND CO-LOCALIZATION) [#3]SUB1 (SUBTILISIN-LIKE PROTEASE MATURED DOWNSTREAM OF ERC VIA PMX) [#1]

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 ERC (PfERC/PF3D7_1108600) was identified as an endoplasmic reticulum-resident calcium-binding protein in asexual stages of P. falciparum. It contains six EF-hand calcium-binding domains and a C-terminal IDEL ER-retention motif. Calcium-binding activity was confirmed by 45Ca2+-blotting, and ER localization was established by co-localization with the known ER protein Pfgrp by confocal immunofluorescence microscopy. Expression was shown to increase with parasite maturity by immunoblot of synchronized parasites. 45Ca2+-blotting, confocal immunofluorescence co-localization with ER marker Pfgrp, immunoblot of synchronized parasites, partial protein sequencing, gene sequencing Molecular and biochemical parasitology High 9364972
2020 Conditional knockdown of ERC (PfERC/PF3D7_1108600) in P. falciparum demonstrated it is essential for asexual growth and specifically required for parasite egress. Knockdown prevented rupture of the parasitophorous vacuole membrane (PVM). Mechanistically, ERC knockdown inhibited proteolytic maturation of the subtilisin-like serine protease SUB1. Using double-mutant parasites, ERC was shown to be required for the proteolytic maturation of the aspartic protease plasmepsin X (PMX), which in turn is required for SUB1 cleavage. Processing of substrates downstream of the proteolytic cascade was also inhibited. ERC knockdown did not affect protein trafficking or calcium storage. Conditional knockdown (inducible knockdown system), double-mutant epistasis analysis, immunofluorescence microscopy, immunoblot for proteolytic maturation, parasitophorous vacuole membrane rupture assay mBio High 32098818
2012 ERC (PfERC/PF3D7_1108600) was identified by chemical proteomics as a P. falciparum protein with high affinity for the endoperoxide structure N-346 (a carboxyamino derivative of the antimalarial N-89). ERC protein levels were decreased upon treatment of parasites with N-89 or its hydroxyl derivative N-251, as shown by proteomic expression profiling. Chemical proteomics (affinity pulldown with endoperoxide-derivatized probe N-346), proteomic expression profiling after drug treatment Journal of proteome research Medium 23061985
2020 ERC (PF3D7_1108600) was shown to associate with the ER-resident serpentine receptor SR10 in P. falciparum by co-localization and co-immunoprecipitation assays. Co-immunoprecipitation, co-localization assay Molecular and biochemical parasitology Medium 32890576
2024 In P. berghei-infected mice treated with the endoperoxide N-89 transdermally, PbERC (the P. berghei ortholog of ERC/PF3D7_1108600) gene expression was suppressed relative to control. Concurrently, expression of egress-related genes plasmepsin X, subtilisin-like protease 1, and merozoite surface protein 1 was suppressed at 12 h. This is consistent with a functional role for ERC upstream of the egress proteolytic cascade, as established in P. falciparum. Quantitative real-time PCR of PbERC and egress-related gene expression after transdermal N-89 treatment in P. berghei-infected mice Parasitology international Low 39740755

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 The CREC family, a novel family of multiple EF-hand, low-affinity Ca(2+)-binding proteins localised to the secretory pathway of mammalian cells. FEBS letters 132 10648803
1997 Identification of an endoplasmic reticulum-resident calcium-binding protein with multiple EF-hand motifs in asexual stages of Plasmodium falciparum. Molecular and biochemical parasitology 66 9364972
2012 Plasmodium falciparum endoplasmic reticulum-resident calcium binding protein is a possible target of synthetic antimalarial endoperoxides, N-89 and N-251. Journal of proteome research 29 23061985
2020 An Endoplasmic Reticulum CREC Family Protein Regulates the Egress Proteolytic Cascade in Malaria Parasites. mBio 27 32098818
1997 Plasmodium falciparum Pfs40, renamed Pf39, is localized to an intracellular membrane-bound compartment and is not sexual stage-specific. Molecular and biochemical parasitology 25 9497061
2021 Calcium in the Backstage of Malaria Parasite Biology. Frontiers in cellular and infection microbiology 13 34395314
2021 A proteomic glimpse into the effect of antimalarial drugs on Plasmodium falciparum proteome towards highlighting possible therapeutic targets. Pathogens and disease 9 33202000
2020 The endoplasmic reticulum-resident serpentine receptor SR10 has important functions for asexual and sexual blood stage development of Plasmodium falciparum. Molecular and biochemical parasitology 2 32890576
2019 Genomic and biological features of Plasmodium falciparum resistance against antimalarial endoperoxide N-89. Gene 2 31377318
2024 The antimalarial activity of transdermal N-89 mediated by inhibiting ERC gene expression in P. Berghei-infected mice. Parasitology international 1 39740755