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Molecular Mechanisms of the Membrane Sculpting ESCRT Pathway

Abstract

The Endosomal Sorting Complex Required for Transport (ESCRT) is an ancient, complex machinery that remodels and scissions cellular membranes. Uniquely, the ESCRTs remodel and scission membranes in a reverse topology – away from the cytosol. Since their discovery the ESCRTs have been identified in a large number of cellular processes, but detailed mechanistic understanding has proven difficult. As a system of over 20 components that rapidly and dynamically rearrange themselves to constrict and scission membranes, the ESCRTs prove a difficult machinery that will require high-quality reconstitutions to study.

In Chapter 1 I provide an introduction to the ESCRTs and describe recent advances toward achieving a consensus on the mechanism of ESCRT-mediated membrane remodeling and scission. In Chapter 2 I discuss the first reconstitution of ESCRT-mediated membrane scission, combining microscopy, microfluidics, and optical trapping to achieve this goal. In Chapter 3 I describe a novel function of the ESCRTs, finding that CHMP1B, IST1, and Spastin are capable of normal-topology membrane scission. Finally, in Chapter 4 I provide an outlook on the remaining challenges in the field, and the approaches that will be crucial for tackling them.

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