PF3D7_0931800

PF3D7_0931800 encodes the β6 subunit of the Plasmodium falciparum 20S proteasome, a structural component of the assembled catalytic core resolved in cryo-EM structures of the Pf20S complex (PMID:26863983, PMID:31384003). Within the core, β6 sits at an inhibitor-binding interface shared with the β5 and β3 subunits: the reversible inhibitor SW584 binds non-covalently at a pocket at the β5/β6/β3 interface, distinct from the catalytic threonine, exploiting structural differences between the Pf and human proteasomes (PMID:39084225). A point mutation in β6 (A117D) confers resistance to the macrocyclic peptide inhibitor TDI-8304, directly establishing that β6 contributes to the Pf20S inhibitor-binding site; the same mutation causes collateral sensitivity by altering proteasome architecture so that the β2 inhibitor WLW-vs binds the β2 and β5 sites more effectively (PMID:38097652). As a core subunit, β6 also participates in the asymmetric engagement of the Pf20S core by the PfPA28 regulator (PMID:31384003). Beyond its structural role in the 20S core and its contribution to the shared inhibitor-binding interface, the catalytic or substrate-specific function of β6 itself has not been individually characterized in the available corpus.

1. 2016 Medium

   Establishing the subunit architecture of the P. falciparum 20S proteasome was needed to locate individual catalytic-core subunits; the high-resolution structure placed β6 within the assembled complex.

   Evidence Cryo-EM single-particle analysis of Pf20S at 3.6 Å with substrate profiling and in vitro inhibitor assays

   PMID:26863983

   Open questions at the time

   • β6-specific catalytic contribution not resolved beyond complex membership
   • no functional data on β6 substrate specificity
2. 2019 Medium

   How the Pf20S core engages its PA28 regulator was unknown; the Pf20S–PfPA28 structure positioned β6 as a core subunit within an asymmetric core–regulator interaction.

   Evidence Cryo-EM of Pf20S–PfPA28 at 3.8–3.9 Å with PfPA28 crystallography, SAXS, MD simulations, and PA28 genetic deletion

   PMID:31384003

   Open questions at the time

   • specific role of β6 in PA28 engagement not individually defined
   • functional consequence of asymmetric regulation for β6 activity unknown
3. 2023 High

   Whether β6 contributes to inhibitor binding was untested; a resistance-conferring β6 A117D mutation demonstrated β6 forms part of the Pf20S inhibitor-binding site and shapes cross-inhibitor sensitivity.

   Evidence Resistance selection in P. falciparum culture plus cryo-EM of wild-type and Pf20Sβ6A117D complexes with the β2 inhibitor WLW-vs

   PMID:38097652

   Open questions at the time

   • mechanism by which A117D remodels the β2/β5 sites for collateral sensitivity not fully resolved
   • physiological cost of β6 A117D on proteasome function untested
4. 2024 High

   Defining a druggable, species-selective pocket required mapping where reversible inhibitors bind; SW584 was shown to bind non-covalently at the β5/β6/β3 interface, confirming β6 as part of a shared inhibitor-binding surface.

   Evidence Cryo-EM of the Pf proteasome–SW584 complex, His8-tagged β7-facilitated purification, and resistance selection identifying Pfβ5 active-site mutations

   PMID:39084225

   Open questions at the time

   • direct β6 contribution to SW584 affinity vs. β5/β3 not deconvoluted
   • no β6 mutant validation of the SW584 pocket

• The intrinsic catalytic activity, substrate specificity, and non-structural roles of the β6 subunit itself remain undefined in the available corpus.
• no β6-specific enzymatic characterization
• no assembly or turnover studies isolating β6
• role of β6 in parasite viability not directly tested