Affinage · Plasmodium

PF3D7_0803800

proteasome subunit beta type-4

Annotated
2026-09-08
6 papers in source corpus 6 papers cited in narrative 6 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PF3D7_0803800 encodes a beta-type subunit of the Plasmodium falciparum 20S proteasome (Pf20S), a multi-subunit proteolytic core; the gene was cloned as a 265-amino-acid member of the 20S proteasome beta-subunit family, encoded by a transcript interrupted by a single intron (PMID:10856507). Cryo-EM structures of the intact Pf20S place this beta-subunit within the assembled catalytic core alongside the other beta-subunits, and reveal active-site architecture in the core that differs from the human enzyme (PMID:26863983). Within the larger complex, Pf20S associates with the PfPA28 regulatory cap, which engages the 20S core asymmetrically and is consistent with a lateral-transfer mechanism for release of degradation products (PMID:31384003). The catalytic and inhibitor-binding chemistry of the core has been mapped extensively at the beta2, beta5, beta6, and beta3 subunits, where species-selective pockets are exploited for antimalarial inhibitor design (PMID:34548400, PMID:38097652, PMID:39084225). Beyond its membership in the Pf20S core established by these structures, the specific catalytic or structural contribution of the PF3D7_0803800 beta-4 subunit as an individual entity has not been resolved in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2000 Medium

    Establishing that P. falciparum possesses this specific proteasome beta-subunit gene defined a candidate component of the parasite's proteolytic machinery at the sequence level.

    Evidence Molecular cloning, cDNA/genomic sequence comparison and Northern blot in P. falciparum

    PMID:10856507

    Open questions at the time
    • No functional or catalytic assay for the subunit
    • Assignment within the assembled complex not shown
    • Whether the subunit is proteolytically active undetermined
  2. 2016 High

    The first cryo-EM structure of the intact Pf20S positioned the beta-subunits within the catalytic core and exposed parasite-specific active-site features distinguishing it from the human proteasome.

    Evidence Cryo-EM single-particle analysis at 3.6 Å of the Pf20S complex in P. falciparum

    PMID:26863983

    Open questions at the time
    • Individual catalytic contribution of the beta-4 subunit not isolated
    • Structure captures the assembled complex, not this subunit in isolation
  3. 2019 High

    Resolving how the PfPA28 regulatory cap docks onto the 20S core clarified the architecture and product-release mechanism of the fuller proteasome assembly containing this subunit.

    Evidence Cryo-EM, PfPA28 crystallography, SAXS, molecular dynamics, and PA28 genetic deletion in P. falciparum

    PMID:31384003

    Open questions at the time
    • Role of the beta-4 subunit specifically in PA28 engagement not defined
    • Functional consequence for this subunit not tested
  4. 2021 High

    Comparing Pf20S and human 20S bound to boronate inhibitors explained species selectivity at the beta5 active site, advancing selective antimalarial proteasome inhibitor design.

    Evidence Cryo-EM of Pf20S with MPI-5 and bortezomib plus biochemical inhibition and resistance profiling in P. falciparum

    PMID:34548400

    Open questions at the time
    • Findings center on beta5, not the beta-4 subunit encoded by PF3D7_0803800
    • No individual functional role for this subunit
  5. 2023 High

    Mapping dual beta2/beta5 engagement of TDI-8304 and a beta6 resistance mutation defined how inhibitor binding and collateral sensitivity distribute across core beta-subunits.

    Evidence Cryo-EM of wild-type and mutant Pf20S with resistance selection and enzymatic/anti-parasite assays in P. falciparum

    PMID:38097652

    Open questions at the time
    • Focused on beta2, beta5, beta6, not the beta-4 subunit
    • No isolated role for PF3D7_0803800
  6. 2024 High

    Identifying a non-covalent inhibitor pocket at the beta5/beta6/beta3 interface expanded the druggable surface of the Pf20S core and confirmed beta5 as the primary pharmacological target.

    Evidence Cryo-EM of Pf20S with SW584, resistance selection, and biochemical assays with His8-tag purification in P. falciparum

    PMID:39084225

    Open questions at the time
    • The characterized interface pocket involves beta5/beta6/beta3, not the beta-4 subunit
    • Contribution of PF3D7_0803800 to this pocket unaddressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • The individual catalytic or structural role of the PF3D7_0803800 beta-4 subunit, distinct from its membership in the Pf20S core, remains unresolved.
  • No subunit-specific catalytic assay
  • No inhibitor characterized as binding this subunit specifically
  • No genetic knockout/knockdown of PF3D7_0803800 alone

Mechanism profile

Synthesis pass · controlled-vocabulary classification
Partners
PFPA28 (PROTEASOME REGULATORY CAP)
Complex memberships
Pf20S-PfPA28 complexProteasome 20S core complex (Pf20S)

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 PF3D7_0803800 (a P. falciparum 20S proteasome beta subunit) was molecularly cloned; the gene encodes a 265-amino-acid protein (predicted MW 30.9 kDa, pI 6.2) with a 156-bp intron 85 bp downstream of the start codon, establishing it as a member of the 20S proteasome beta-subunit family. Molecular cloning, cDNA/genomic DNA sequence comparison, Northern blot International journal for parasitology Medium 10856507
2016 Cryo-EM structure of the P. falciparum 20S proteasome (Pf20S) at 3.6 Å resolution placed the beta-subunits (including the beta-type-4 subunit encoded by PF3D7_0803800) within the complex and revealed active-site architecture; the beta2 active site was found to be unusually open compared to the human ortholog, informing subunit-selective inhibitor design. Cryo-electron microscopy and single-particle analysis at 3.6 Å resolution Nature High 26863983
2019 Cryo-EM structures of the Pf20S–PfPA28 complex (one and two PA28 caps, resolved at 3.9 Å and 3.8 Å) showed that PA28 binds the 20S core asymmetrically, strongly engaging subunits on only one side; molecular dynamics simulations indicated conformational flexibility at the interface, supporting a lateral-transfer mechanism for release of proteasome degradation products. Cryo-EM single-particle analysis, crystal structure of PfPA28, SAXS, molecular dynamics simulations, genetic deletion of PA28 Nature microbiology High 31384003
2021 Cryo-EM structures of Pf20S and human 20S in complex with amino-amide boronate inhibitor MPI-5, and of Pf20S with bortezomib, revealed differences in beta5 active-site binding modes that explain selectivity of these inhibitors for the parasite proteasome over the human enzyme. Cryo-EM structure determination, biochemical inhibition assays, resistance profiling Proceedings of the National Academy of Sciences of the United States of America High 34548400
2023 High-resolution cryo-EM structures of Pf20S with macrocyclic inhibitor TDI-8304 showed that TDI-8304 binds both the beta2 and beta5 subunits of wild-type Pf20S; a resistance mutation in the beta6 subunit (A117D) eliminates TDI-8304 binding while conferring collateral sensitivity to the beta2 inhibitor WLW-vs, which in the mutant binds both beta2 and beta5. Cryo-EM structure determination, resistance mutation selection, enzymatic and anti-parasite activity assays Nature communications High 38097652
2024 Cryo-EM structure of Pf20S in complex with piperidine carboxamide SW584 revealed non-covalent binding in a previously unexplored pocket at the beta5/beta6/beta3 subunit interface (distal from the catalytic threonine); point mutations in the beta5 active site conferred resistance to SW584, confirming beta5 as the primary pharmacological target. Cryo-EM structure determination, resistance selection, biochemical inhibition assays, His8-tag proteasome purification Cell chemical biology High 39084225

Source papers

Stage 0 corpus · 6 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Structure- and function-based design of Plasmodium-selective proteasome inhibitors. Nature 196 26863983
2019 The structure of the PA28-20S proteasome complex from Plasmodium falciparum and implications for proteostasis. Nature microbiology 37 31384003
2021 Design of proteasome inhibitors with oral efficacy in vivo against Plasmodium falciparum and selectivity over the human proteasome. Proceedings of the National Academy of Sciences of the United States of America 33 34548400
2023 Structures revealing mechanisms of resistance and collateral sensitivity of Plasmodium falciparum to proteasome inhibitors. Nature communications 21 38097652
2024 Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria. Cell chemical biology 11 39084225
2000 Molecular cloning of a gene encoding a 20S proteasome beta subunit from Plasmodium falciparum. International journal for parasitology 8 10856507