HIV-1 budding is facilitated by the host ESCRT (Endosomal Sorting Complex Required for Transport) pathway. The ESCRT pathway also provides membrane fission activities during the cellular processes of cytokinesis, MVB vesicle formation, and shedding vesicle release. The structural protein of the virus, HIV-1 p6Gag, contains two late domain motifs that interact directly with the early-acting ESCRT factors TSG101/ESCRT-I and ALIX, and thereby help recruit the pathway to the neck of the budding virus. Perhaps the important outstanding question in this area is how the ESCRT machinery can draw closed the necks of budding viruses, vesicles, and intercellular bridges. Studies from a number of laboratories have established that the late-acting ESCRT-III family proteins form filaments that are intimately involved in these membrane remodeling processes. We (and others) have previously determined crystal structures of ESCRT-III proteins in their monomeric, autoinhibited conformations and we are now attempting to understand the molecular architectures of the polymeric ESCRT-III filaments. In a collaboration with Adam Frost, we have determined a subnanometer resolution cryo-EM reconstruction of the helical filaments formed by co-assembly of the IST1 and CHMP1B ESCRT-III protein pair. The reconstruction reveals that IST1 and CHMP1B copolymerize into a novel paired, helical filament. I will describe the structure and will also describe reconstitution experiments in which helical arrays of recombinant IST1 filaments bind and tubulate membranes with a topology that matches ESCRT-mediated membrane remodeling. Together, these experiments suggest how ESCRT-III subunits can form filaments, assemble into helices, and bind and remodel membranes during HIV-1 budding and cell division.

ESCRT pathway in HIV budding and cell division

247th National Meeting (2014)

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