Summary
A bioRxiv preprint reports that DFCP1 assembles into a helical coat that concentrates the membrane lipid PI3P and helps organise sites where cells repair damaged lysosomes.
A bioRxiv preprint reports that DFCP1, a protein associated with the endoplasmic reticulum (ER), assembles into a helical coat around a narrow membrane tube. The researchers’ structural analyses, simulations and cell experiments point to the coat acting as a barrier that concentrates the membrane lipid PI3P at ER sites involved in repairing damaged lysosomes.
Lysosomes are membrane-bound compartments that break down and recycle cellular material. Repairing damage to their membranes is important for maintaining them. The ER also forms specialised local regions, or microdomains, that help organise processes including lysosome repair. How such regions retain the molecules needed for a local task has been an open question.
How DFCP1 creates a local membrane boundary
The researchers determined the structure of full-length human DFCP1 bound to membranes using cryo-electron tomography and single-particle cryo-electron microscopy. They found that DFCP1 units assemble into tetramers, which stack into a helical coat around a constricted membrane tube.
Different parts of the protein contribute to the assembly: its ATPase domains form the coat’s organising core, its ER-targeting domains insert into the membrane’s outer leaflet, and its FYVE domains bind PI3P. PI3P is a lipid found in cell membranes that can act as a recognition signal for proteins such as DFCP1.
In coarse-grained molecular dynamics simulations, the coat behaved not just as a structure following the membrane’s shape but as a barrier to lipid movement. The simulations showed that it almost completely blocked PI3P from diffusing past the filament, concentrating the lipid beneath the coat. The authors propose that this boundary helps keep locally made lipids near repair sites instead of allowing them to disperse into the wider ER membrane.
Mutations link the coat to repair activity
Cell experiments connected the structure to lysosome repair. Mutations that disrupted DFCP1 assembly, membrane insertion or PI3P binding each impaired repair. The researchers also found that DFCP1 assembly was needed for the focal recruitment of VPS13C, a lipid transporter, to these sites.
Together, the findings offer a physical explanation for how an ER microdomain could be organised: DFCP1 forms a collar that helps retain a particular lipid locally and supports recruitment of a transporter involved at repair sites. The work is reported as a bioRxiv preprint.