SPC1

PF3D7_1433600 (SPC1/PfSP21) is the catalytic subunit of the Plasmodium falciparum signal peptidase complex that cleaves N-terminal signal peptides from secretory preproteins, an activity demonstrated directly by cleavage of a signal peptidase cleavage site-containing substrate in vitro (PMID:18054093). Its endopeptidase activity is upregulated by protein kinase C-mediated phosphorylation (PMID:18054093). Consistent with a role in co-translational signal peptide processing, SPC1 localizes to the parasite endoplasmic reticulum (PMID:18054093), and it is required for intra-erythrocytic growth, since dsRNA-mediated knockdown reducing endogenous SPC1 protein specifically inhibits parasite proliferation in culture (PMID:18054093). All available characterization derives from a single study; beyond these findings, no further mechanistic detail on SPC1 has been characterized in the available corpus.

1. 2007 Medium

   Whether SPC1/PfSP21 is enzymatically responsible for signal peptide removal was unresolved; demonstrating direct cleavage established it as the catalytic signal peptidase activity in the parasite.

   Evidence in vitro peptide cleavage assay with recombinant PfSP21 on a substrate carrying a signal peptidase cleavage site, in P. falciparum

   PMID:18054093

   Open questions at the time

   • no independent replication beyond the single study
   • cleavage of authentic full-length preprotein substrates not shown
   • contribution of other complex subunits to catalysis not resolved
2. 2007 Medium

   How SPC1 activity is regulated was unknown; PKC phosphorylation was shown to upregulate its cleavage activity, linking signal peptidase function to a kinase-dependent post-translational control.

   Evidence in vitro phosphorylation by protein kinase C followed by measurement of peptide cleavage activity, in P. falciparum

   PMID:18054093

   Open questions at the time

   • phosphorylation sites on SPC1 not mapped
   • no evidence this regulation operates in vivo
   • identity of the physiological kinase not established
3. 2007 Medium

   The subcellular site of SPC1 action was undefined; ER localization placed its activity at the expected compartment for co-translational signal peptide cleavage.

   Evidence immunofluorescence with anti-PfSP21 antibodies in intraerythrocytic stages, in P. falciparum

   PMID:18054093

   Open questions at the time

   • single IFA with no functional consequence linked to localization
   • membrane topology and complex assembly at the ER not characterized
4. 2007 Medium

   Whether SPC1 is essential for the parasite was unknown; knockdown-induced growth inhibition established it as required for intra-erythrocytic proliferation.

   Evidence dsRNA-mediated gene silencing with growth assay and immunoblot confirmation of reduced PfSP21, in P. falciparum

   PMID:18054093

   Open questions at the time

   • no independent genetic confirmation (e.g. conditional knockout or complementation)
   • molecular basis of the growth defect (accumulation of unprocessed preproteins) not directly demonstrated

• The native composition, stoichiometry, and in vivo substrate repertoire of the SPC1-containing signal peptidase complex remain unestablished.
• no interacting subunits of the complex characterized in the corpus
• no structural model of SPC1
• no endogenous substrate set defined