ISWI

PF3D7_0624600 (ISWI) is a nuclear chromatin-associated ATPase of Plasmodium falciparum that localizes to a distinct nuclear sub-compartment (PMID:19765590) and participates in chromatin-remodeling and transcriptional-regulatory networks in the parasite (PMID:36379669, PMID:39636094). It is recruited to active var gene promoter regions (PMID:36379669) and physically associates with the PfMORC chromatin complex linked to heterochromatin and subtelomeric var gene regulation (PMID:39636094); in the P. berghei ortholog (PBANKA_1123500), ISWI is co-identified within the AP2-TR/MORC transcriptional repressor complex during the intraerythrocytic cycle (PMID:41484140). Its regulatory context is further defined by phosphorylation: ISWI is a phosphoprotein in blood-stage parasites (PMID:19450262) whose phosphorylation status changes upon depletion of the phosphatase PfPPM2 (PMID:40410154). Beyond membership in these chromatin complexes and its regulated phosphorylation, the direct enzymatic activity, substrate specificity, and loss-of-function phenotype of PF3D7_0624600 itself have not been characterized in the available corpus.

1. 2009 Low

   Establishing that ISWI is post-translationally modified addressed whether the remodeler is subject to signaling control in blood-stage parasites.

   Evidence Phosphoprotein affinity enrichment with LC/MS/MS from trophozoite-stage P. falciparum

   PMID:19450262

   Open questions at the time

   • Phosphosites and their functional consequence not defined
   • No kinase assigned
   • Single screen without functional follow-up
2. 2009 Medium

   Defining where ISWI resides addressed whether the ATPase occupies a specialized nuclear territory consistent with a chromatin role.

   Evidence GFP/HA epitope tagging with fluorescence microscopy in P. falciparum

   PMID:19765590

   Open questions at the time

   • The specific chromatin loci occupied were not resolved here
   • No link to a defined remodeling activity
3. 2012 Low

   Co-purification with CK2 regulatory subunits placed ISWI within CK2-associated chromatin assembly/remodeling complexes, connecting the remodeler to a kinase network.

   Evidence IP of HA-tagged PfCK2β1/PfCK2β2 followed by mass spectrometry

   PMID:22293287

   Open questions at the time

   • No reciprocal pulldown of ISWI
   • Direct binding vs. shared complex membership not distinguished
   • Functional consequence of the association unknown
4. 2016 Low

   Testing plasmodium nucleosomes as substrates for a human ISWI-type enzyme addressed whether parasite chromatin is intrinsically remodelable, though it concerns the substrate rather than PF3D7_0624600 itself.

   Evidence In vitro remodeling assays with recombinant human Snf2H on P. falciparum vs. human nucleosomes; hybrid octamer and bandshift experiments

   PMID:28033404

   Open questions at the time

   • Not performed with PF3D7_0624600 protein
   • Enzymatic parameters of the parasite ISWI itself unmeasured
5. 2019 Low

   Correlating ISWI transcript timing with ap2-g de-repression addressed whether the remodeler is deployed at the point of sexual commitment.

   Evidence Time-course RNA-seq across gametocytogenesis stages in P. falciparum

   PMID:31795940

   Open questions at the time

   • Transcript correlation only, no functional test
   • Causal relationship to ap2-g activation not established
6. 2020 Medium

   Direct chromatin occupancy mapping addressed whether ISWI is physically present at var gene regulatory DNA, linking it to antigenic variation control.

   Evidence dCas9-based chromatin isolation and protein identification at active var promoters in P. falciparum

   PMID:36379669

   Open questions at the time

   • Whether ISWI recruitment activates or maintains var expression not shown
   • Direct vs. complex-mediated occupancy unresolved
7. 2024 Medium

   Co-purification studies across multiple chromatin machineries addressed which complexes ISWI belongs to, defining its interaction landscape.

   Evidence IP-MS of PfMORC, TurboID proximity labeling of PfSET10, and reciprocal pulldown of PfEAF2 (PfSWR1/NuA4) in P. falciparum; RIME of PbAP2-TR/PbMORC and PbARID in P. berghei

   PMID:38554111 PMID:38564734 PMID:39445823 PMID:39636094 PMID:41484140

   Open questions at the time

   • Most interactions are single Co-IP/proximity hits without reciprocal validation for ISWI
   • P. berghei associations (AP2-TR/MORC, ARID) reported at low confidence scores
   • Whether ISWI is a stable core subunit or transient associate of these complexes unresolved
8. 2025 Low

   Perturbing a phosphatase addressed how ISWI phosphorylation is controlled, placing it downstream of PfPPM2 signaling in blood-stage chromatin regulation.

   Evidence Quantitative phosphoproteomics of PfPPM2-knockdown P. falciparum parasites

   PMID:40410154

   Open questions at the time

   • Direct dephosphorylation of ISWI by PfPPM2 not demonstrated
   • Functional consequence of altered phosphorylation on remodeling activity unknown

• The intrinsic ATPase/remodeling activity, substrate specificity, and loss-of-function phenotype of PF3D7_0624600 itself remain undefined.
• No knockout/knockdown phenotype for ISWI
• No demonstration of nucleosome remodeling by the parasite protein
• Role at var promoters vs. sexual commitment vs. heterochromatin not functionally dissected