The ESCRT pathway mediates membrane remodeling during enveloped virus budding, cytokinesis, and intralumenal endosomal vesicle formation. Late in the pathway, a subset of membrane-associated ESCRT-III proteins utilize terminal amphipathic "MIM1" helices to bind and recruit VPS4 ATPases via their MIT domains. This study from the Sundquist lab reports that VPS4 MIT domains also bind a second, "MIM2" motif found in a different subset of ESCRT-III subunits. The solution structure of the VPS4 MIT-CHMP6 MIM2 complex revealed that MIM2 elements bind in extended conformations along the groove between the first and third helices of the MIT domain. Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting and HIV-1 budding. These observations indicate that MIT-MIM2 interactions are likely to be common throughout the ESCRT pathway and elsewhere, and we suggest how these interactions could contribute to a mechanism in which VPS4 and ESCRT-III proteins function together to constrict the necks of budding vesicles.

Structure showing how the MIM2 element from human CHMP6 (blue) binds in the helix 1/3 groove of the MIT domain from VPS4A.