Structure and function of the DFCP1 membrane barrier responsible for ER microdomain organization in lysosome repair
- 1UC Berkeley
Abstract
The endoplasmic reticulum (ER) forms specialized microdomains that organize autophagy, lipid droplet formation, and the repair of damaged lysosomes. The PI3P-binding protein DFCP1/ZFYVE1 marks these microdomains, raising the question as to whether and how one protein could define such a subcompartment. Here we determine the structure of full-length human DFCP1 bound to membranes by cryo-electron tomography and single-particle cryo-electron microscopy. DFCP1 assembles into a helical coat, built from tetramers that stack around a constricted membrane tube. Its ATPase domains form the organizing core of the helix, while its ER-targeting domains insert deeply into the outer leaflet, and its FYVE domains grip PI3P. Coarse-grained molecular dynamics simulations show that the coat does not simply follow the curvature of the membrane but acts as a barrier to lipid diffusion, almost completely blocking the movement of its cognate lipid PI3P past the filament and concentrating it beneath the coat. Point mutations that break the assembly, membrane-insertion or PI3P-binding interfaces each impair lysosomal repair in cells, and the assembly is also required for the focal recruitment of the lipid transporter VPS13C. We propose that DFCP1 collars fence off a specialized ER microdomain, so that locally made lipids can reach sites of repair rather than escaping into bulk ER.
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BibTeX
@misc{cui2026structure,
title = {{Structure and function of the DFCP1 membrane barrier responsible for ER microdomain organization in lysosome repair}},
author = {Z. Cui and K. Palacio-Rodriguez and E. Herrmann and A. Kourniotis and M. Radulovic and S. Pust and K. Tapia and C. Raiborg and G. Hummer and H. Stenmark and J. H. Hurley},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.19.759623},
url = {https://www.biorxiv.org/content/10.64898/2026.10.19.759623v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Structure and function of the DFCP1 membrane barrier responsible for ER microdomain organization in lysosome repair
AU - Z. Cui
AU - K. Palacio-Rodriguez
AU - E. Herrmann
AU - A. Kourniotis
AU - M. Radulovic
AU - S. Pust
AU - K. Tapia
AU - C. Raiborg
AU - G. Hummer
AU - H. Stenmark
AU - J. H. Hurley
PY - 2026
DA - 2026/10/19
PB - bioRxiv
DO - 10.64898/2026.10.19.759623
UR - https://www.biorxiv.org/content/10.64898/2026.10.19.759623v1
AB - The endoplasmic reticulum (ER) forms specialized microdomains that organize autophagy, lipid droplet formation, and the repair of damaged lysosomes. The PI3P-binding protein DFCP1/ZFYVE1 marks these microdomains, raising the question as to whether and how one protein could define such a subcompartment. Here we determine the structure of full-length human DFCP1 bound to membranes by cryo-electron tomography and single-particle cryo-electron microscopy. DFCP1 assembles into a helical coat, built from tetramers that stack around a constricted membrane tube. Its ATPase domains form the organizing core of the helix, while its ER-targeting domains insert deeply into the outer leaflet, and its FYVE domains grip PI3P. Coarse-grained molecular dynamics simulations show that the coat does not simply follow the curvature of the membrane but acts as a barrier to lipid diffusion, almost completely blocking the movement of its cognate lipid PI3P past the filament and concentrating it beneath the coat. Point mutations that break the assembly, membrane-insertion or PI3P-binding interfaces each impair lysosomal repair in cells, and the assembly is also required for the focal recruitment of the lipid transporter VPS13C. We propose that DFCP1 collars fence off a specialized ER microdomain, so that locally made lipids can reach sites of repair rather than escaping into bulk ER.
ER -