RPN10

RPN10 (PF3D7_0807800) is a subunit of the 19S regulatory particle of the Plasmodium 26S proteasome that functions as an intrinsic ubiquitin receptor for the degradation machinery (PMID:26639022). It carries two ubiquitin-interacting motif (UIM) domains, of which UIM2 is the functional receptor: in vitro, PfUIM2 (alone or in combination with UIM1) binds both K48- and K63-linked polyubiquitin chains and pulls down a broad range of ubiquitin conjugates from parasite extracts, whereas UIM1 alone does not bind (PMID:26639022). Beyond direct chain recognition, RPN10 serves as the proteasomal docking site for the substrate-shuttle protein PfDsk2, binding the PfDsk2 UBL domain with an affinity comparable to the human system despite structural differences at the interface (PMID:32057831). In a Xenopus oocyte heterologous system, RPN10 is found in a 19S assembly containing P. berghei Rpt3 but lacking PP1c, indicating the Rpt3–PP1c interaction occurs outside the RPN10-associated regulatory particle (PMID:41373862).

1. 2015 Medium

   It was unknown how the plasmodial proteasome recognizes ubiquitinated substrates; this work established RPN10 as the intrinsic ubiquitin receptor and pinpointed UIM2 as the responsible domain.

   Evidence Recombinant domain-specific constructs in Ni-NTA pull-down assays with K48/K63 polyubiquitin chains and P. falciparum extracts

   PMID:26639022

   Open questions at the time

   • No structure of the RPN10 UIM–ubiquitin complex
   • In vitro binding not linked to substrate turnover in intact parasites
   • Functional distinction between UIM1 and UIM2 in vivo not tested
2. 2020 Medium

   Whether Plasmodium uses shuttle factors to deliver substrates to the proteasome was open; this work showed RPN10 is the docking site for the PfDsk2 shuttle protein via its UBL domain.

   Evidence 1.30 Å crystal structure of PfDsk2 UBL plus dissociation-constant measurements of the PfDsk2–RPN10 interaction

   PMID:32057831

   Open questions at the time

   • Binding interface inferred from structural comparison rather than direct RPN10 mutagenesis
   • No co-structure of the RPN10–PfDsk2 complex
   • Physiological consequence of the shuttle interaction not tested in parasites
3. 2025 Low

   The composition of the Rpt3-containing 19S particle relative to PP1c was unclear; this work placed RPN10 in a 19S assembly with Rpt3 that excludes PP1c, localizing the Rpt3–PP1c interaction outside the proteasome.

   Evidence Co-immunoprecipitation with anti-Xenopus RPN10 antibody in a Xenopus oocyte heterologous expression system (P. berghei Rpt3)

   PMID:41373862

   Open questions at the time

   • Single Co-IP in a heterologous system, not validated in Plasmodium
   • Only indirectly characterizes RPN10's own role
   • No reciprocal IP or native complex confirmation

• The in vivo requirement of RPN10 for parasite proteasome function, its essentiality, and the cellular consequences of disrupting its ubiquitin-receptor or shuttle-docking activities remain uncharacterized in the available corpus.
• No genetic knockdown/knockout phenotype for RPN10 in Plasmodium
• No structural model of RPN10 itself
• Contribution of RPN10 to antimalarial proteasome-inhibitor sensitivity unknown