PEX26-F51L Research | Regina Ring & Yehuda Dinaii
Computational and structural analysis of a peroxisomal disease variant
July 27, 2026
Overview
Peroxisome biogenesis factor 26 (PEX26) is a tail-anchored peroxisomal membrane protein that recruits and anchors the hexameric AAA-ATPase complex PEX1โPEX6 to the cytosolic face of the peroxisome. The complex uses ATP hydrolysis to retrotranslocate the import receptor PEX5 back to the cytosol, enabling repeated rounds of peroxisomal matrix protein import. In yeast, Pex15 is the functional homologue of human PEX26.
The homozygous missense variant F51L in PEX26 is associated with peroxisome biogenesis disorders on the Zellweger spectrum, and has been linked to sensorineural hearing loss. It was first described in 2019 in four siblings from an Ashkenazi Jewish family [Tanaka et al. (2019)]. To our knowledge, only six individuals worldwide are known to carry this mutation: the four siblings reported in that study, and our two daughters.
๐ฌ PeroxiBot (NotebookLM)
Chat with an AI trained on the PEX26-F51L literature.
Last updated: July 27, 2026
Key Questions
- How does F51L alter the structure and dynamics of the PEX26 cytosolic domain?
- Does the mutation affect recruitment or binding of the PEX1/PEX6 complex?
- How is this related to sensorineural hearing loss?
What We Do
We use AlphaFold 3 for structure prediction and CHARMM-GUI for the peroxisome membrane to build accurate structural models of both the wild-type and the PEX26-F51L variant.
We modeled the PEX1/PEX6/PEX26 double ring D1-D2 domains with a portion of PEX5 inserted in the central pore.
We explore conformational ensembles using BioEmu.
We use GROMACS molecular dynamics simulations to study the effect of physical conditions such as temperature on protein behavior, and to characterize how the PEX26-F51L mutation affects peroxisome function and ultimately leads to hearing loss.
We collaborate with university laboratories specializing in peroxisome biology and genetic hearing loss. We have contributed patient-derived fibroblasts to these collaborations and have a mouse model of the mutation.
Our long-term goal is to advance a therapeutic pathway for this condition. We hope that our work will also contribute to the broader understanding of more severe peroxisomal diseases on the Zellweger spectrum.
Status
Work in progress โ structural models and ensemble analysis ongoing.