Membrane constriction and thinning by sequential ESCRT-III polymerization

Abstract

<jats:title>Abstract</jats:title><jats:p>The Endosomal Sorting Complexes Required for Transport (ESCRTs) mediate diverse membrane remodeling events. These activities typically require ESCRT-III proteins to stabilize negatively-curved membranes, although recent work has indicated that certain ESCRT-IIIs also participate in positive-curvature membrane shaping reactions. ESCRT-IIIs polymerize into membrane-binding filaments, but the structural basis for negative versus positive membrane curvature shaping by these proteins remains poorly understood. To learn how ESCRT-IIIs shape membranes, we determined structures of human membrane-bound CHMP1B-only, membrane-bound CHMP1B+IST1, and IST1-only filaments by electron cryomicroscopy. Our structures show how CHMP1B first polymerizes into a single-stranded helical filament, shaping membranes into moderate-curvature tubules. Subsequently, IST1 assembles a second strand upon the CHMP1B filament, further constricting the membrane tube and reducing its diameter nearly to the fission point. Each step of constriction, moreover, thins the underlying bilayer and lowers the barrier to membrane fission. Together, our structures reveal how a two-component, sequential polymerization mechanism drives membrane tubulation, tube constriction, and bilayer thinning.</jats:p>

Photocatalytic plant LPOR forms helical lattices that shape membranes for chlorophyll synthesis

“…The overall diameter of the filament was ~24 nm, and the distance between outer leaflet headgroups was ~12 nm versus ~6 nm between the inner leaflet headgroups. Such a thin bilayer thickness, just ~3 nm, is consistent with previous observations of highly constricted membranes 13 .…”

Bacterial Vipp1 and PspA are members of the ancient ESCRT-III membrane-remodelling superfamily

“…Helix a5 was then angled at near right angles from helix a4 in both Vipp1 and ESCRT-III proteins. In addition to these core common helices a1-a5 between Vipp1 and CHMP1B (17,23), the Vipp1 monomer includes an N-terminal helix a0 (aa 1-22) that extends perpendicular to the hairpin and mediates membrane binding in both PspA and Vipp1 systems (24)(25)(26)(27). Helix a0 is not observed in CHMP1B, but it is shared by ESCRT-III proteins such as yeast Snf7…”

“…Interestingly, in the context of ESCRT-III proteins, similar C-terminal extensions that include a-helical elements have been shown to function as protein-protein interaction motifs (MIM) (4). For CHMP1B, its C-terminal extension binds the ESCRT-III homologue Ist1 to form a dual stranded copolymer (23).…”

NPC1-mTORC1 signaling Couples Cholesterol Sensing to Organelle Homeostasis and is a Targetable Pathway in Niemann-Pick type C

“…Recently, it has emerged that the lysosomal limiting membrane is susceptible to damage resulting from undigested/undigestible substrates that accumulate within the lumen (Jia et al, 2020;Maejima et al, 2013; upon loss of NPC1 function might compromise the integrity of the lysosomal membrane. An early detection system provided by the Endosomal Sorting Complex Required for Transport (ESCRT) III proteins detects 'microtears' in the lysosomal membrane and repairs them via a membrane scission process that is thought to topologically resemble ESCRT III-mediated intraluminal vesicle budding during endosomal maturation (Nguyen et al, 2020;Radulovic et al, 2018;Schöneberg et al, 2017;Skowyra et al, 2018). Accordingly, our proteomics analysis found enrichment of the ESCRT III-interacting protein ALIX (also known as PDCD6IP), along with ESCRT III components CHMP1A and IST1 in NPC1-defective over wild-type lysosomes (Table S1) (Figure 2A).…”