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bioRxiv · 10.64898/2026.09.01.748678

Structural mechanism of nuclear membrane sealing by LEM2-ESCRT-III

Jordan, M. A.·Palacio-Rodriguez, K.·Adakkattil, R.·Welsch, S.·Niese, L.·LaJoie, D.·von der Weth, E.·Alves Melo, A.·Redlingshoefer, L.·Otsuka, S.·Diez, S.·Hummer, G.·Von Appen, A.
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Abstract

In open mitosis, re-establishing nucleocytoplasmic compartmentalization requires the LEM2-ESCRT machinery to coordinate spindle clearance with sealing of the remaining nuclear envelope pores. The structural basis of this topologically unique and fundamental membrane-remodeling process is poorly understood. Here, we combine biochemical reconstitution, cryo-electron tomography, subtomogram averaging and large-scale molecular dynamics simulations to define the structural mechanism of nuclear membrane sealing. We structurally resolve that LEM2s winged-helix domain (WH) co-polymerizes with the ESCRT-II/III protein CHMP7 to form a membrane-bound scaffold whose geometry is progressively remodeled by downstream ESCRT-III proteins as it transitions from the flat membrane surrounding the pore towards the negatively curved membrane neck. In parallel, LEM2 positions its intrinsically disordered low-complexity domain within the pore, where condensation around spindle microtubules mechanically couples the membrane-ESCRT-LEM2 scaffold to the spindle and narrows the remaining diffusion path, restoring compartmentalization before membrane closure is complete. Remarkably, the LEM2-WH domain alone forms tightly constricted membrane tubes, coating the negatively curved inner surface, revealing an intrinsic membrane-remodeling activity of the receptor itself. Together, our work establishes a structural framework for how receptor-ESCRT co-polymerization, low complexity domain-mediated sealing and receptor-driven membrane remodeling guide nuclear-envelope pores from spindle-containing openings to terminal constriction and fusion.

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Jordan, M. A., Palacio-Rodriguez, K., Adakkattil, R., Welsch, S., Niese, L., LaJoie, D., von der Weth, E., Alves Melo, A., Redlingshoefer, L., Otsuka, S., Diez, S., Hummer, G., Von Appen, A.. 2026-09-03. Structural mechanism of nuclear membrane sealing by LEM2-ESCRT-III. https://doi.org/10.64898/2026.09.01.748678

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