SEC63

PF3D7_1318800 (PfSec63) is a putative transmembrane ER-resident HSP40/J-domain co-chaperone assigned to the Sec-family protein translocation machinery of Plasmodium falciparum on the basis of bioinformatic and comparative-genomics analyses (PMID:17919451, PMID:26167469). Within this framework it is placed alongside the PfSec61 translocon and is proposed to function together with the ER-lumenal chaperone PfHsp70-2 (a BiP homologue) to drive co- and post-translational translocation of signal-peptide-containing proteins into the ER (PMID:26167469, PMID:20719001). It has additionally been described as an auxiliary component of specialized Sec61 channels dedicated to translocation of PEXEL-containing exported proteins, where plasmepsin V is co-associated (PMID:34440567). Its role as a J-domain activator of PfHsp70-2 has been modeled in silico, and the PfHsp70-2–PfSec63 complex has served as a virtual-screening target (PMID:37621993). No direct biochemical, genetic, or structural experiment on PF3D7_1318800 itself is present in the available corpus; every claim above rests on computational prediction, expression-based network inference, or review-level extrapolation, and the two candidate interactors (MAL8P1.153 and PFI1780w) reported for it are predicted rather than experimentally validated (PMID:20719001).

1. 2007 Low

   Establishing whether P. falciparum possesses a Sec63 orthologue was the first step in defining its ER translocation machinery; a genome-wide search identified PF3D7_1318800 as a putative member of the Sec61/Sec62/Sec63 complex.

   Evidence Bioinformatics/comparative genomics of the P. falciparum genome

   PMID:17919451

   Open questions at the time

   • Computational prediction only; no experimental confirmation that PF3D7_1318800 is expressed as a translocon component
   • No demonstration of physical association with Sec61
   • No localization data
2. 2010 Low

   To place PF3D7_1318800 in a functional context, expression profiling and network construction annotated it as a transmembrane ER HSP40 for signal-peptide protein translocation and predicted candidate partners within the parasite chaperone network.

   Evidence Expression profiling of clinical isolates with Cytoscape-based interactome network inference

   PMID:20719001

   Open questions at the time

   • Predicted interactors MAL8P1.153 and PFI1780w were not validated by Co-IP or pulldown
   • Membrane topology and ER residence not experimentally shown
   • Functional role in translocation not tested
3. 2015 Low

   A synthesis of chaperone-pathway data proposed PF3D7_1318800 as a membrane-bound co-chaperone acting with PfHsp70-2 (BiP) and the PfSec61 translocon to mediate ER secretory-pathway protein translocation.

   Evidence Literature review citing chaperone assays and Sec61 pathway analysis

   PMID:26167469

   Open questions at the time

   • No direct experiment on PF3D7_1318800 reported
   • PfSec63–PfHsp70-2 functional coupling not biochemically demonstrated
   • J-domain stimulation of BiP ATPase not measured
4. 2021 Low

   Refining the substrate specificity question, PF3D7_1318800 was described as an auxiliary factor of specialized Sec61 channels dedicated to PEXEL-containing exported proteins, distinguishing them from canonical channels handling PNEPs.

   Evidence Review of published genetic and biochemical translocon-composition data

   PMID:34440567

   Open questions at the time

   • Review-level claim; no direct experiment on PF3D7_1318800
   • Physical co-association with plasmepsin V at these channels not shown for PF3D7_1318800 itself
   • Selectivity for PEXEL versus PNEP substrates not tested experimentally
5. 2023 Low

   To move toward a druggable model, in silico docking modeled PF3D7_1318800 as a J-domain partner of PfHsp70-2 and used the complex for virtual screening, nominating compounds that engage the complex or its J domain.

   Evidence Molecular docking and molecular dynamics simulation (in silico)

   PMID:37621993

   Open questions at the time

   • Computational only; the PfHsp70-2–PfSec63 interaction was not biochemically validated
   • Compound binding and complex-stabilizing effects untested in cells or in vitro
   • No structural determination of PF3D7_1318800
6. 2024 Low

   Cross-species extrapolation identified a P. knowlesi orthologue (PKNH_1419600, 82% identity) proposed to activate the lumenal PkHSP70 during ER translocation, extending the predicted Sec63–BiP relationship beyond P. falciparum.

   Evidence Comparative genomics and sequence identity analysis (bioinformatics)

   PMID:39596368

   Open questions at the time

   • No experiments performed in P. knowlesi
   • Orthologue function inferred solely from sequence identity
   • PkHSP70 activation by PKNH_1419600 not demonstrated

• Whether PF3D7_1318800 physically associates with PfSec61 and PfHsp70-2, whether its J domain stimulates BiP ATPase activity, and whether it is required for translocation of PEXEL-exported proteins all remain experimentally unaddressed.
• No Co-IP, pulldown, or reciprocal interaction validation
• No conditional knockdown/knockout to test translocation function
• No structural or topology data for the protein