PF3D7_0415800

PIC3 (PF3D7_0415800) is a component of the PhIL1-associated protein complex that resides in the inner membrane complex (IMC) of P. falciparum and functions in erythrocyte invasion by the merozoite (PMID:34324609, PMID:33830607). It was defined as a member of the PhIL1-interacting protein set through PhIL1 immunoprecipitation-mass spectrometry in gametocytes (PMID:28985225) and through BioID proximity proteomics in asexual blood stages, with endogenous GFP-tagging confirming its IMC localization (PMID:33830607); this PhIL1 complex co-exists with the glideosome motor complex in the merozoite IMC (PMID:34324609). Conditional depletion of PIC3 impairs merozoite segmentation and abolishes the reorientation/gliding step that follows initial erythrocyte attachment, so that invasion fails while initial RBC attachment is unaffected — placing PIC3 specifically in the post-attachment reorientation step required for productive invasion (PMID:34324609). Beyond its complex membership and this invasion phenotype, no further biochemical activity, structural detail, or direct binding partner of PIC3 has been characterized in the available corpus.

1. 2017 Low

   To begin defining the composition of the PhIL1 IMC complex, it was necessary to identify its associated proteins; this placed PIC3 within the PhIL1-interacting candidate set.

   Evidence PhIL1 immunoprecipitation coupled with mass spectrometry in P. falciparum gametocytes

   PMID:28985225

   Open questions at the time

   • Single Co-IP/MS experiment identifying membership only, with no functional characterization of PIC3 itself
   • Direct versus indirect association with PhIL1 not resolved
   • Finding was made in gametocytes, leaving the asexual-stage role undefined
2. 2021 Medium

   To confirm PIC3 is a genuine IMC-resident protein rather than a Co-IP artifact, orthogonal proximity labeling and direct tagging were needed; this validated both its association with PhIL1 and its subcellular localization.

   Evidence BioID proximity-dependent biotinylation proteomics with PhIL1 as bait plus endogenous GFP-tagging and fluorescence microscopy in asexual blood-stage P. falciparum

   PMID:33830607

   Open questions at the time

   • Proximity labeling does not establish direct physical contact between PIC3 and PhIL1
   • No stoichiometry or architecture of the complex determined
   • Single lab
3. 2021 Medium

   To move from association to function, PIC3 needed to be genetically depleted; this established that PIC3 is required for merozoite segmentation and for the post-attachment reorientation/gliding step of invasion, pinpointing where in the invasion sequence it acts.

   Evidence Conditional knockdown/disruption with invasion, reorientation/gliding, and segmentation assays, and immunoprecipitation to define complex membership, in P. falciparum merozoites

   PMID:34324609

   Open questions at the time

   • The molecular activity of PIC3 that drives reorientation is unknown
   • How PIC3 mechanistically couples the PhIL1 complex to the glideosome motor is undefined
   • Whether the segmentation and reorientation defects are separable functions is not resolved

• The biochemical activity of PIC3, its direct binding partners within the PhIL1 complex, and the mechanism by which it enables merozoite reorientation remain undefined.
• No enzymatic or structural function assigned to PIC3
• No direct (versus proximity/co-purifying) interaction partner mapped
• Molecular link between PIC3, the PhIL1 complex, and the glideosome motor not established