Structural mechanism of nuclear membrane sealing by LEM2-ESCRT-III
- 1Max Planck Institute of Molecular Cell Biology and Genetics
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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BibTeX
@misc{jordan2026structural,
title = {{Structural mechanism of nuclear membrane sealing by LEM2-ESCRT-III}},
author = {M. A. Jordan and K. Palacio-Rodriguez and R. Adakkattil and S. Welsch and L. Niese and D. LaJoie and E. von der Weth and A. Alves Melo and L. Redlingshoefer and S. Otsuka and S. Diez and G. Hummer and A. Von Appen},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.01.748678},
url = {https://www.biorxiv.org/content/10.64898/2026.09.01.748678v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Structural mechanism of nuclear membrane sealing by LEM2-ESCRT-III
AU - M. A. Jordan
AU - K. Palacio-Rodriguez
AU - R. Adakkattil
AU - S. Welsch
AU - L. Niese
AU - D. LaJoie
AU - E. von der Weth
AU - A. Alves Melo
AU - L. Redlingshoefer
AU - S. Otsuka
AU - S. Diez
AU - G. Hummer
AU - A. Von Appen
PY - 2026
DA - 2026/09/01
PB - bioRxiv
DO - 10.64898/2026.09.01.748678
UR - https://www.biorxiv.org/content/10.64898/2026.09.01.748678v1
AB - 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.
ER -