HMGB3

PF3D7_1205800 (HMGB3) is a large (~2,284 amino acid) predicted P. falciparum HMG box protein distinguished from the smaller single-box HMGB1 and HMGB2 paralogs by two HMG box domains and an additional putative Myb domain (PMID:16607015, PMID:33585284). The available evidence positions HMGB3 in the context of nuclear chromatin regulation rather than assigning it a direct biochemical function: it co-enriches with the transcription factor AP2-I on regulatory motif 028-containing promoter DNA alongside bromodomain and SWIB/MDM2 proteins (PMID:29649445), and it co-purifies with PfEAF2 in the context of the PfSWR1 chromatin remodeling complex (PMID:38564734). HMGB3 was also recovered as a PfHSP70-2 interactor in a yeast two-hybrid screen (PMID:32529065) and detected in sporozoite proteomes across Plasmodium species (PMID:33585284). No direct loss-of-function experiment or in vitro biochemical characterization of HMGB3 itself has been reported in the available corpus; all functional inference rests on computational domain prediction and association with named partners and complexes.

1. 2006 Low

   Establishing that the P. falciparum HMGB family includes a distinct large member answered whether all Plasmodium HMGB proteins are functionally equivalent, revealing HMGB3 as structurally unique.

   Evidence Computational sequence/domain analysis of the P. falciparum HMGB family

   PMID:16607015

   Open questions at the time

   • Domain content is predicted only, with no experimental validation of DNA binding or Myb-domain function
   • No evidence for the biological process HMGB3 participates in
2. 2018 Low

   Identifying HMGB3 among proteins captured on a specific regulatory motif addressed where in the genome it might act, linking it to promoter-associated chromatin regulation with AP2-I.

   Evidence DNA affinity pulldown with motif-028 probes and mass spectrometry

   PMID:29649445

   Open questions at the time

   • Single pulldown without functional follow-up on HMGB3 itself
   • Does not establish direct DNA binding by HMGB3 versus indirect recruitment
   • No demonstration that HMGB3 loss affects AP2-I target expression
3. 2020 Low

   A yeast two-hybrid screen added HMGB3 to the interactome of PfHSP70-2, raising the question of whether HMGB3 is a chaperone client or partner.

   Evidence Yeast two-hybrid interaction screen

   PMID:32529065

   Open questions at the time

   • Single-method interaction with no reciprocal or in vivo validation
   • Functional consequence of the HSP70-2 interaction unknown
4. 2021 Low

   Detecting HMGB3 in sporozoite proteomes across species addressed its stage expression and, combined with its unique Myb-binding domain, motivated a candidate transcription-factor role in the sporozoite.

   Evidence Mass spectrometry of sporozoite proteomes across Plasmodium species

   PMID:33585284

   Open questions at the time

   • Proteomic presence does not establish transcriptional activity
   • Myb-domain role is inferred from computational annotation, not tested
5. 2024 Low

   Reciprocal PfEAF2 pulldowns placed HMGB3 within the PfSWR1 chromatin remodeling complex context, refining its inferred association from promoter DNA to a defined remodeling machinery.

   Evidence Reciprocal affinity pulldown/mass spectrometry with PfEAF2 as bait

   PMID:38564734

   Open questions at the time

   • HMGB3 recovered as a minor associated factor without direct functional role in the complex
   • No stoichiometry or direct binding data
   • No loss-of-function test of HMGB3 within PfSWR1

• Whether HMGB3 has any intrinsic DNA-binding, chromatin-remodeling, or transcriptional activity, and whether it is essential at any parasite stage, remains undetermined absent any direct loss-of-function or in vitro biochemical experiment.
• No knockout, knockdown, or complementation of HMGB3
• No in vitro reconstitution of HMG-box DNA binding or Myb-domain function
• No demonstration that any co-purification reflects a direct interaction