Changes in ESCRT-III filament geometry drive membrane remodelling and fission in silico

Abstract

BackgroundESCRT-III is a membrane remodelling filament with the unique ability to cut membranes from the inside of the membrane neck. It is essential for the final stage of cell division, the formation of vesicles, the release of viruses, and membrane repair. Distinct from other cytoskeletal filaments, ESCRT-III filaments do not consume energy themselves, but work in conjunction with another ATP-consuming complex. Despite rapid progress in describing the cell biology of ESCRT-III, we lack an understanding of the physical mechanisms behind its force production and membrane remodelling.ResultsHere we present a minimal coarse-grained model that captures all the experimentally reported cases of ESCRT-III driven membrane sculpting, including the formation of downward and upward cones and tubules. This model suggests that a change in the geometry of membrane bound ESCRT-III filaments—from a flat spiral to a 3D helix—drives membrane deformation. We then show that such repetitive filament geometry transitions can induce the fission of cargo-containing vesicles.ConclusionsOur model provides a general physical mechanism that explains the full range of ESCRT-III-dependent membrane remodelling and scission events observed in cells. This mechanism for filament force production is distinct from the mechanisms described for other cytoskeletal elements discovered so far. The mechanistic principles revealed here suggest new ways of manipulating ESCRT-III-driven processes in cells and could be used to guide the engineering of synthetic membrane-sculpting systems.

Human ESCRT-III polymers assemble on positively curved membranes and induce helical membrane tube formation

“…However, in this report, the global membrane shape transformation was essentially attributed to filament doublets nonhomogeneously distributed around the tube, with different adhesion energy depending on the face in contact with the membrane. The authors propose that the possibility for the filaments to tilt and roll on the membrane for optimizing their binding can generate torque on the filament axis that can produce constriction and scission 60 . This type of structure, however, represents only a very minor fraction of the organizations that we have observed with human ESCRTs, suggesting that other mechanisms can also shape vesicles in to pipe surfaces.…”

An ESCRT-III Polymerization Sequence Drives Membrane Deformation and Fission

“…A recent computational model, in which driven sequential changes in the polymer orientation relative to the membrane caused flat spirals to transition into conical and helical polymers, could explain how a shift in polymer properties imposed by changes in its composition might drive filament deformation (Harker-Kirschneck et al, 2019). Consistently, cryoelectron microscopy (cryo-EM) of Snf7-Vps2-Vps24 and Snf7-Vps2-Did2 patch assays and model of sequential ESCRT-III recruitment.…”

“…This observed twist in the helical structure corresponds to the tilt of each subunit imposed in the simulations. We therefore extended the earlier model (Harker-Kirschneck et al, 2019) to include staged assembly/disassembly of multiple filaments as observed in our experiments ( Figure 5A). First, we modeled the recruitment of tilted (helical) Vps2-Did2 polymers to the flat membranebound spirals (Snf7-Vps2-Vps24) before simulating removal of the flat filament.…”

“…The filament subunits were represented by the 3-beaded model, as previously developed by us (Harker-Kirschneck et al, 2019). The target geometry of the protein filaments was a ring, which was controlled by the 9 bonds between consecutive filament subunits.…”

Bacterial Vipp1 and PspA are members of the ancient ESCRT-III membrane-remodelling superfamily

“…As we show here, both Vipp1 and CHMP1B also have a shoulder joint located at the C-terminus of helix a2 (Hinge1). Collectively, these conserved hinges enable the polymers to assume forms that differ widely in curvature and tilt, including a broad variety of complex 3D structures like domes (35). In addition, both Vipp1 and CHMP1B form polymers through side-by-side packing of the hairpin motif and through helix a5 contacting the hairpin of neighbouring subunits j+3 or j+4, respectively.…”