Computational Model of Membrane Fission Catalyzed by ESCRT-III

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Abstract
ESCRT-III proteins catalyze membrane fission during multi vesicular body biogenesis, budding of some enveloped viruses and cell division. We suggest and analyze a novel mechanism of membrane fission by the mammalian ESCRT-III subunits CHMP2 and CHMP3. We propose that the CHMP2-CHMP3 complexes self-assemble into hemi-spherical dome-like structures within the necks of the initial membrane buds generated by CHMP4 filaments. The dome formation is accompanied by the membrane attachment to the dome surface, which drives narrowing of the membrane neck and accumulation of the elastic stresses leading, ultimately, to the neck fission. Based on the bending elastic model of lipid bilayers, we determine the degree of the membrane attachment to the dome enabling the neck fission and compute the required values of the protein-membrane binding energy. We estimate the feasible values of this energy and predict a high efficiency for the CHMP2-CHMP3 complexes in mediating membrane fission. We support the computational model by electron tomography imaging of CHMP2-CHMP3 assemblies in vitro. We predict a high efficiency for the CHMP2-CHMP3 complexes in mediating membrane fission. Membrane fission is a key step of fundamental intracellular processes such as endocytosis, membrane trafficking, cytokinesis and virus budding. The fission reaction requires substantial energy inputs provided by specialized proteins. Recently, the ESCRT-III proteins have been implicated in membrane budding and fission involved in multivesicular body formation, cytokinesis and virus budding. The ESCRT-III proteins self-assemble into circular filaments and flat spirals in the membrane plane and generate tubular structures with dome-like end caps. We suggest and elaborate computationally on a mechanism by which the ESCRT-III complexes can drive membrane fission. The essence of the mechanism is in generation in the course of membrane attachment to the dome-like surface of an ESCRT-III assembly of a thin membrane neck accumulating large elastic stresses. Relaxation of these stresses can drive the neck fission and formation of separate vesicles of biologically relevant sizes. Estimations of the membrane affinity to the protein surface required for the neck fission to occur and comparison of these values with the experimentally expected values justify quantitatively the proposed mechanism and demonstrate that ESCRT-III assemblies must be highly effective in promoting membrane fission.