Structural basis of CHMP2A–CHMP3 ESCRT-III polymer assembly and membrane cleavage

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Azad, Kimi | Guilligay, Delphine | Boscheron, Cecile | Maity, Sourav | de Franceschi, Nicola | Sulbaran, Guidenn | Effantin, Gregory | Wang, Haiyan | Kleman, Jean-Philippe | Bassereau, Patricia | Schoehn, Guy | Roos, Wouter | Desfosses, Ambroise | Weissenhorn, Winfried

Edité par CCSD ; Nature Publishing Group -

International audience. The endosomal sorting complex required for transport (ESCRT) is a highly conserved protein machinery that drives a divers set of physiological and pathological membrane remodeling processes. However, the structural basis of ESCRT-III polymers stabilizing, constricting and cleaving negatively curved membranes is yet unknown. Here we present cryo-EM structures of membrane-coated CHMP2A-CHMP3 filaments from Homo sapiens of two different diameters at 3.3 and 3.6 Å resolution. The structures reveal helical filaments assembled by CHMP2A-CHMP3 heterodimers in the open ESCRT-III conformation, which generates a partially positive charged membrane interaction surface, positions short N-terminal motifs for membrane interaction and the C-terminal VPS4 target sequence toward the tube interior. Inter-filament interactions are electrostatic, which may facilitate filament sliding upon VPS4-mediated polymer remodeling. Fluorescence microscopy as well as high-speed atomic force microscopy imaging corroborate that VPS4 can constrict and cleave CHMP2A-CHMP3 membrane tubes. We therefore conclude that CHMP2A-CHMP3-VPS4 act as a minimal membrane fission machinery.

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