ESCRT model · A biophysical model for ESCRT-III mediated membrane scission

A biophysical model for ESCRT-III mediated membrane scission

The ESCRT-III complex is an evolutionary conserved protein machinery that mediates membrane remodeling and scission in many important physiological and pathological cellular contexts, such as cell division, HIV virus release, multivesicular bodies formation, nuclear membrane repair, dendritic spines regulation, and others. A subset of ESCRT-III proteins, namely CHMP4B, CHMP3 and CHMP2A/B, appear to be strictly required in all these processes, indicating that they might constitute the minimal scission machinery. ESCRT mis-function has been linked with the pathogenesis of several diseases, including the neurodegenerative disease Fronto-Temporal Dementia (FTD). All these cellular processes involve membrane remodeling/scission activities that are topologically equivalent, and are characterized by the so-called “inverse topology”, in which the ESCRT-III complex assemble and function inside a membrane tube or neck. Thus, the complex is expected to display a membrane curvature preference, in particular it has been proposed to assemble preferentially on negatively curved membranes. This, however, is not supported by convincing experimental evidence, and despite several model being proposed over the past decade, the molecular mechanism of ESCRT-III function is still obscure. This lack of experimental data is mainly due to the technical challenge of reconstituting the ESCRT-III complex on a negatively curved membrane. This question is very relevant, since ESCRT-III might represent potential therapeutic targets for treatment of a number of diseases. The original aim of this proposal was to develop a novel in vitro approach to reconstitute and characterize the assembly and mechanism of function of the ESCRT-III complex on a negatively curved membrane, thus reproducing the correct membrane topology present in vivo.

Data: CORDIS, © European Union