PEX10

PEX10 is an integral peroxisomal membrane protein required for peroxisomal matrix-protein import, defined by two transmembrane segments and a cytosol-facing C3HC4 zinc-finger RING motif whose integrity is essential for function (PMID:9700193, PMID:9683594). It operates downstream of PEX5 receptor docking: loss of PEX10 does not prevent PEX5 association with peroxisomes, and PEX10 instead physically interacts with PEX12 through PEX12's zinc-RING domain, with PEX10 overexpression suppressing a PEX12 missense allele—establishing PEX10 and PEX12 as functionally coupled RING partners (PMID:10562279). The RING domain is the critical catalytic element: zinc-coordination mutants impair function, and abolishing Zn2+ binding in the plant ortholog produces deformed peroxisomes, defective peroxisome–chloroplast contact, and failed photorespiration, linking the RING to ubiquitination of PEX5 (PMID:10862081, PMID:20679226). In prostate cancer cells PEX10 is transcriptionally induced through an androgen-receptor/FOXA1 enhancer and lowers intracellular ROS, so that AR blockade by enzalutamide suppresses PEX10 and sensitizes cells to ROS-activating agents (PMID:39097593). Beyond these findings, the detailed enzymatic mechanism of PEX10-mediated ubiquitin transfer in mammalian cells has not been directly characterized in the available corpus.

1. 1998 High

   Established that PEX10 is a peroxisomal membrane protein whose RING domain is required to support matrix-protein import, defining it as a biogenesis factor rather than an imported matrix protein.

   Evidence Epitope-tagged topology mapping, subcellular fractionation, and functional complementation of PBD group B/CG7 fibroblasts with wild-type and RING-deleted cDNAs

   PMID:9683594 PMID:9700193

   Open questions at the time

   • Molecular activity of the RING domain not yet defined
   • Direct binding partners at the membrane not identified
2. 1999 High

   Placed PEX10 in a defined import step by showing it acts downstream of PEX5 docking and physically partners with PEX12, answering where in the import cascade PEX10 functions.

   Evidence Two-hybrid, blot overlay, co-immunoprecipitation, in vivo genetic suppression of a PEX12 mutation, and PEX5 peroxisome-association assay

   PMID:10562279

   Open questions at the time

   • Biochemical consequence of the PEX10–PEX12 interaction not resolved
   • Whether the pair acts catalytically not addressed here
3. 2000 Medium

   Refined which residues of the RING domain carry function by showing graded activity loss across missense versus null alleles, connecting genotype to residual biological activity.

   Evidence Site-directed mutagenesis and functional complementation in PEX10-deficient patient fibroblasts

   PMID:10862081

   Open questions at the time

   • Complementation results confounded by read-through/alternative-translation artifacts noted by authors
   • Single-lab assay without orthogonal biochemical confirmation
4. 2010 Medium

   Linked the RING domain to PEX5 ubiquitination and revealed the N-terminal cytosolic domain controls peroxisome shape and inter-organelle contact, broadening PEX10's role beyond import to organelle morphology and metabolism.

   Evidence Dominant-negative zinc-binding mutants in Arabidopsis with confocal morphology, metabolite analysis, and photorespiration gas-exchange assays

   PMID:20679226

   Open questions at the time

   • Plant ortholog context limits direct extrapolation to mammalian PEX10
   • Direct demonstration of PEX10-catalyzed PEX5 ubiquitination not shown
5. 2024 Medium

   Identified a transcriptional input and a physiological output for PEX10, showing AR/FOXA1 drives its expression and PEX10 buffers intracellular ROS, connecting peroxisomal function to redox control in cancer cells.

   Evidence ChIP/enhancer analysis of AR-FOXA1 at the PEX10 locus, ROS assays, enzalutamide treatment, and PEX10 knockdown/overexpression with viability readouts

   PMID:39097593

   Open questions at the time

   • Mechanism linking PEX10 to ROS reduction not defined
   • Single cancer-cell context
6. 2025 Medium

   Provided structural framing for the Pex2/Pex10/Pex12 RING complex acting as an E3 ligase that assembles with Pex5/Pex8 to initiate PTS1-receptor recycling after cargo translocation.

   Evidence Cryo-EM of Pex8–Pex5 complex with yeast complementation and interface mutagenesis (preprint)

   Open questions at the time

   • PEX10's specific role inferred from complex membership rather than directly interrogated
   • Preprint, not peer-reviewed
   • Mammalian relevance not established

• The direct enzymatic activity of mammalian PEX10 as a ubiquitin ligase—its E2 partner, substrate-engagement mechanism, and the structure of the assembled Pex2/Pex10/Pex12 complex—remains uncharacterized in the available corpus.
• No reconstituted ubiquitination assay with mammalian PEX10
• Cognate E2 enzyme not identified
• No mammalian structure of the assembled RING complex