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- PDB-8cqr: Cryo-EM structure of the NINJ1 filament -

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Basic information

Entry
Database: PDB / ID: 8cqr
TitleCryo-EM structure of the NINJ1 filament
ComponentsNinjurin-1
KeywordsMEMBRANE PROTEIN / Polymer / Cell death
Function / homology
Function and homology information


ferroptosis / cell adhesion mediator activity / pyroptotic cell death / leukocyte chemotaxis involved in inflammatory response / membrane destabilizing activity / cytolysis / positive regulation of toll-like receptor 4 signaling pathway / programmed necrotic cell death / tissue regeneration / muscle cell differentiation ...ferroptosis / cell adhesion mediator activity / pyroptotic cell death / leukocyte chemotaxis involved in inflammatory response / membrane destabilizing activity / cytolysis / positive regulation of toll-like receptor 4 signaling pathway / programmed necrotic cell death / tissue regeneration / muscle cell differentiation / cellular hyperosmotic response / heterotypic cell-cell adhesion / synaptic membrane / lipopolysaccharide binding / protein homooligomerization / positive regulation of inflammatory response / positive regulation of angiogenesis / nervous system development / angiogenesis / killing of cells of another organism / cell adhesion / extracellular region / plasma membrane
Similarity search - Function
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsDegen, M.D. / Hiller, S.H. / Maier, T.M.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Swiss Nanoscience Institute Switzerland
CitationJournal: Nature / Year: 2023
Title: Structural basis of NINJ1-mediated plasma membrane rupture in cell death.
Authors: Morris Degen / José Carlos Santos / Kristyna Pluhackova / Gonzalo Cebrero / Saray Ramos / Gytis Jankevicius / Ella Hartenian / Undina Guillerm / Stefania A Mari / Bastian Kohl / Daniel J ...Authors: Morris Degen / José Carlos Santos / Kristyna Pluhackova / Gonzalo Cebrero / Saray Ramos / Gytis Jankevicius / Ella Hartenian / Undina Guillerm / Stefania A Mari / Bastian Kohl / Daniel J Müller / Paul Schanda / Timm Maier / Camilo Perez / Christian Sieben / Petr Broz / Sebastian Hiller /
Abstract: Eukaryotic cells can undergo different forms of programmed cell death, many of which culminate in plasma membrane rupture as the defining terminal event. Plasma membrane rupture was long thought to ...Eukaryotic cells can undergo different forms of programmed cell death, many of which culminate in plasma membrane rupture as the defining terminal event. 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-1 (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.
History
DepositionMar 7, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 17, 2023Provider: repository / Type: Initial release
Revision 1.1May 24, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.pdbx_database_id_DOI ..._citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2May 31, 2023Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.3Jul 12, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.4Jul 24, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond / em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
E: Ninjurin-1
D: Ninjurin-1
A: Ninjurin-1
B: Ninjurin-1
F: Ninjurin-1
C: Ninjurin-1


Theoretical massNumber of molelcules
Total (without water)98,2206
Polymers98,2206
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area14170 Å2
ΔGint-135 kcal/mol
Surface area33510 Å2

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Components

#1: Protein
Ninjurin-1 / Nerve injury-induced protein 1


Mass: 16369.932 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NINJ1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q92982

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: helical reconstruction

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Sample preparation

ComponentName: NINJ1 / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 3500 nm / Nominal defocus min: 200 nm
Image recordingElectron dose: 47 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARC3.2, 3.3particle selection
4cryoSPARC3.2, 3.3CTF correction
11cryoSPARC3.2, 3.3classification
12cryoSPARC3.2, 3.33D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -1.05 ° / Axial rise/subunit: 20.95 Å / Axial symmetry: C1
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 709840 / Symmetry type: HELICAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0024782
ELECTRON MICROSCOPYf_angle_d0.4256510
ELECTRON MICROSCOPYf_dihedral_angle_d11.2961656
ELECTRON MICROSCOPYf_chiral_restr0.035834
ELECTRON MICROSCOPYf_plane_restr0.003792

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