---
_id: '13096'
abstract:
- lang: eng
  text: Eukaryotic cells can undergo different forms of programmed cell death, many
    of which culminate in plasma membrane rupture as the defining terminal event1,2,3,4,5,6,7.
    Plasma membrane rupture was long thought to be driven by osmotic pressure, but
    it has recently been shown to be in many cases an active process, mediated by
    the protein ninjurin-18 (NINJ1). Here we resolve the structure of NINJ1 and the
    mechanism by which it ruptures membranes. Super-resolution microscopy reveals
    that NINJ1 clusters into structurally diverse assemblies in the membranes of dying
    cells, in particular large, filamentous assemblies with branched morphology. A
    cryo-electron microscopy structure of NINJ1 filaments shows a tightly packed fence-like
    array of transmembrane α-helices. Filament directionality and stability is defined
    by two amphipathic α-helices that interlink adjacent filament subunits. The NINJ1
    filament features a hydrophilic side and a hydrophobic side, and molecular dynamics
    simulations show that it can stably cap membrane edges. The function of the resulting
    supramolecular arrangement was validated by site-directed mutagenesis. Our data
    thus suggest that, during lytic cell death, the extracellular α-helices of NINJ1
    insert into the plasma membrane to polymerize NINJ1 monomers into amphipathic
    filaments that rupture the plasma membrane. The membrane protein NINJ1 is therefore
    an interactive component of the eukaryotic cell membrane that functions as an
    in-built breaking point in response to activation of cell death.
acknowledged_ssus:
- _id: NMR
- _id: LifeSc
acknowledgement: "This work was supported by the Deutsche Forschungsgemeinschaft under
  Germany’s Excellence Strategy EXC 2075–390740016 and the Stuttgart Center for Simulation
  Science (SC SimTech) to K.P., by ERC-CoG 770988 (InflamCellDeath) and SNF Project
  funding (310030B_198005, 310030B_192523) to P.B., by the Swiss Nanoscience Institute
  and the Swiss National Science Foundation via the NCCR AntiResist (180541) to S.H.
  and the NCCR Molecular Systems Engineering (51NF40-205608) to D.J.M., by the Helmholtz
  Young Investigator Program of the Helmholtz Association to C.S., by the SNF Professorship
  funding (PP00P3_198903) to C.P., EMBO postdoctoral fellowship ALTF 27-2022 to E.H.
  and by the Scientific Service Units of IST Austria through resources provided by
  the NMR and Life Science Facilities to P.S. Molecular dynamics simulations were
  performed on the HoreKa supercomputer funded by the Ministry of Science, Research
  and the Arts Baden-Württemberg and by the Federal Ministry of Education and Research.
  The authors thank the BioEM Lab of the Biozentrum, University of Basel for support;
  V. Mack, K. Shkarina and J. Fricke for technical support; D. Ricklin and S. Vogt
  for peptide synthesis; P. Pelczar for support with animals; S.-J. Marrink and P.
  Telles de Souza for supply with Martini3 parameters and scripts; and P. Radler und
  M. Loose for help with QCM. Fig. 4g and Extended Data Fig. 1a were in part created
  with BioRender.com.\r\nOpen access funding provided by University of Basel."
article_processing_charge: Yes (via OA deal)
article_type: original
author:
- first_name: Morris
  full_name: Degen, Morris
  last_name: Degen
- first_name: José Carlos
  full_name: Santos, José Carlos
  last_name: Santos
- first_name: Kristyna
  full_name: Pluhackova, Kristyna
  last_name: Pluhackova
- first_name: Gonzalo
  full_name: Cebrero, Gonzalo
  last_name: Cebrero
- first_name: Saray
  full_name: Ramos, Saray
  last_name: Ramos
- first_name: Gytis
  full_name: Jankevicius, Gytis
  last_name: Jankevicius
- first_name: Ella
  full_name: Hartenian, Ella
  last_name: Hartenian
- first_name: Undina
  full_name: Guillerm, Undina
  id: bb74f472-ae54-11eb-9835-bc9c22fb1183
  last_name: Guillerm
- first_name: Stefania A.
  full_name: Mari, Stefania A.
  last_name: Mari
- first_name: Bastian
  full_name: Kohl, Bastian
  last_name: Kohl
- first_name: Daniel J.
  full_name: Müller, Daniel J.
  last_name: Müller
- first_name: Paul
  full_name: Schanda, Paul
  id: 7B541462-FAF6-11E9-A490-E8DFE5697425
  last_name: Schanda
  orcid: 0000-0002-9350-7606
- first_name: Timm
  full_name: Maier, Timm
  last_name: Maier
- first_name: Camilo
  full_name: Perez, Camilo
  last_name: Perez
- first_name: Christian
  full_name: Sieben, Christian
  last_name: Sieben
- first_name: Petr
  full_name: Broz, Petr
  last_name: Broz
- first_name: Sebastian
  full_name: Hiller, Sebastian
  last_name: Hiller
citation:
  ama: Degen M, Santos JC, Pluhackova K, et al. Structural basis of NINJ1-mediated
    plasma membrane rupture in cell death. <i>Nature</i>. 2023;618:1065-1071. doi:<a
    href="https://doi.org/10.1038/s41586-023-05991-z">10.1038/s41586-023-05991-z</a>
  apa: Degen, M., Santos, J. C., Pluhackova, K., Cebrero, G., Ramos, S., Jankevicius,
    G., … Hiller, S. (2023). Structural basis of NINJ1-mediated plasma membrane rupture
    in cell death. <i>Nature</i>. Springer Nature. <a href="https://doi.org/10.1038/s41586-023-05991-z">https://doi.org/10.1038/s41586-023-05991-z</a>
  chicago: Degen, Morris, José Carlos Santos, Kristyna Pluhackova, Gonzalo Cebrero,
    Saray Ramos, Gytis Jankevicius, Ella Hartenian, et al. “Structural Basis of NINJ1-Mediated
    Plasma Membrane Rupture in Cell Death.” <i>Nature</i>. Springer Nature, 2023.
    <a href="https://doi.org/10.1038/s41586-023-05991-z">https://doi.org/10.1038/s41586-023-05991-z</a>.
  ieee: M. Degen <i>et al.</i>, “Structural basis of NINJ1-mediated plasma membrane
    rupture in cell death,” <i>Nature</i>, vol. 618. Springer Nature, pp. 1065–1071,
    2023.
  ista: Degen M, Santos JC, Pluhackova K, Cebrero G, Ramos S, Jankevicius G, Hartenian
    E, Guillerm U, Mari SA, Kohl B, Müller DJ, Schanda P, Maier T, Perez C, Sieben
    C, Broz P, Hiller S. 2023. Structural basis of NINJ1-mediated plasma membrane
    rupture in cell death. Nature. 618, 1065–1071.
  mla: Degen, Morris, et al. “Structural Basis of NINJ1-Mediated Plasma Membrane Rupture
    in Cell Death.” <i>Nature</i>, vol. 618, Springer Nature, 2023, pp. 1065–71, doi:<a
    href="https://doi.org/10.1038/s41586-023-05991-z">10.1038/s41586-023-05991-z</a>.
  short: M. Degen, J.C. Santos, K. Pluhackova, G. Cebrero, S. Ramos, G. Jankevicius,
    E. Hartenian, U. Guillerm, S.A. Mari, B. Kohl, D.J. Müller, P. Schanda, T. Maier,
    C. Perez, C. Sieben, P. Broz, S. Hiller, Nature 618 (2023) 1065–1071.
date_created: 2023-05-28T22:01:04Z
date_published: 2023-06-29T00:00:00Z
date_updated: 2023-11-14T11:49:21Z
day: '29'
ddc:
- '570'
department:
- _id: PaSc
doi: 10.1038/s41586-023-05991-z
external_id:
  isi:
  - '000991386800011'
file:
- access_level: open_access
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  creator: dernst
  date_created: 2023-11-14T11:48:18Z
  date_updated: 2023-11-14T11:48:18Z
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file_date_updated: 2023-11-14T11:48:18Z
has_accepted_license: '1'
intvolume: '       618'
isi: 1
language:
- iso: eng
license: https://creativecommons.org/licenses/by/4.0/
month: '06'
oa: 1
oa_version: Published Version
page: 1065-1071
publication: Nature
publication_identifier:
  eissn:
  - 1476-4687
  issn:
  - 0028-0836
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
scopus_import: '1'
status: public
title: Structural basis of NINJ1-mediated plasma membrane rupture in cell death
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 618
year: '2023'
...