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- EMDB-54277: Cryo-EM structure of DISC1 core -

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Basic information

Entry
Database: EMDB / ID: EMD-54277
TitleCryo-EM structure of DISC1 core
Map dataSharpened map
Sample
  • Complex: Tetrameric complex of mDISC1 core
    • Protein or peptide: Disrupted in schizophrenia 1 homolog
KeywordsScaffold / complex / tetramer / coiled coil / UVR domain / psychiatric disorder / STRUCTURAL PROTEIN
Function / homology
Function and homology information


pyramidal neuron migration to cerebral cortex / mitochondrial calcium ion homeostasis / cell proliferation in forebrain / central region of growth cone / cerebral cortex radially oriented cell migration / regulation of dendritic spine development / dynein complex / regulation of synapse maturation / intermediate filament cytoskeleton / non-motile cilium assembly ...pyramidal neuron migration to cerebral cortex / mitochondrial calcium ion homeostasis / cell proliferation in forebrain / central region of growth cone / cerebral cortex radially oriented cell migration / regulation of dendritic spine development / dynein complex / regulation of synapse maturation / intermediate filament cytoskeleton / non-motile cilium assembly / protein localization to centrosome / regulation of postsynapse organization / positive regulation of ubiquitin-dependent protein catabolic process / kinesin complex / positive regulation of cell-matrix adhesion / positive regulation of neuroblast proliferation / ciliary base / regulation of neuron projection development / detection of temperature stimulus involved in sensory perception of pain / microtubule organizing center / TOR signaling / cilium assembly / response to electrical stimulus / canonical Wnt signaling pathway / kinesin binding / positive regulation of Wnt signaling pathway / positive regulation of axon extension / regulation of synaptic transmission, glutamatergic / positive regulation of neuron projection development / GABA-ergic synapse / microtubule cytoskeleton organization / neuron migration / synaptic vesicle / intracellular protein localization / nervous system development / presynapse / cell body / molecular adaptor activity / microtubule / postsynaptic density / ciliary basal body / axon / centrosome / protein-containing complex binding / perinuclear region of cytoplasm / glutamatergic synapse / mitochondrion / identical protein binding / cytosol
Similarity search - Function
Disrupted in schizophrenia 1
Similarity search - Domain/homology
Disrupted in schizophrenia 1 homolog
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsZhou JC
Funding support United Kingdom, 1 items
OrganizationGrant numberCountry
Wellcome Trust United Kingdom
CitationJournal: Nat Commun / Year: 2026
Title: The schizophrenia associated protein DISC1 forms a multivalent tetrameric hub via conserved UVR dimers.
Authors: Jin Chuan Zhou / Jiri Kratochvil / Fei Ye / Kamel El Omari / Philipp Kukura / Mingjie Zhang / Elena Seiradake /
Abstract: DISC1 is a pleiotropic protein with essential roles in neuronal proliferation and migration, intracellular signalling and cargo transport. It associates with a diverse array of partner molecules in ...DISC1 is a pleiotropic protein with essential roles in neuronal proliferation and migration, intracellular signalling and cargo transport. It associates with a diverse array of partner molecules in these contexts. Mutations at the DISC1 locus are strongly associated with a spectrum of mental illnesses such as schizophrenia and depression. Despite its clinical relevance, the molecular architecture and function of DISC1 have remained largely elusive. We present a cryo-EM structure of the entire conserved core region of DISC1. The structure reveals an intricate homotetrameric assembly that harbours conserved bacteria-derived UVR domains. Four of these domains, one from each monomer, mediate extensive contacts forming two asymmetric dimer units. The dimers in turn interface with each other at two distinct coiled coil domains to achieve a two-fold symmetric tetramer. Mutational analysis shows that this tetrameric architecture enables DISC1 to simultaneously bind multiple copies of NDE1 client protein. Importantly, tetramerization and partner binding are structurally independent functions of DISC1. Altogether, our study provides a compelling molecular model of an ancient bacteria protein fold participating in the assembly of a multivalent mammalian scaffold hub that can coordinate multiple partner molecules.
History
DepositionJul 5, 2025-
Header (metadata) releaseMay 6, 2026-
Map releaseMay 6, 2026-
UpdateMay 6, 2026-
Current statusMay 6, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_54277.png

Downloads & links

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Map

FileDownload / File: emd_54277.map.gz / Format: CCP4 / Size: 343 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 448 pix.
= 474.88 Å		1.06 Å/pix.
x 448 pix.
= 474.88 Å		1.06 Å/pix.
x 448 pix.
= 474.88 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.06 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.036542155 - 2.0234613
Average (Standard dev.)0.00025089743 (±0.01042919)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions448448448
Spacing448448448
CellA=B=C: 474.87997 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Raw, non-sharpened map

Fileemd_54277_additional_1.map
AnnotationRaw, non-sharpened map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B

Fileemd_54277_half_map_1.map
AnnotationHalf map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map A

Fileemd_54277_half_map_2.map
AnnotationHalf map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Tetrameric complex of mDISC1 core

EntireName: Tetrameric complex of mDISC1 core
Components
  • Complex: Tetrameric complex of mDISC1 core
    • Protein or peptide: Disrupted in schizophrenia 1 homolog

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Supramolecule #1: Tetrameric complex of mDISC1 core

SupramoleculeName: Tetrameric complex of mDISC1 core / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 170 KDa

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Macromolecule #1: Disrupted in schizophrenia 1 homolog

MacromoleculeName: Disrupted in schizophrenia 1 homolog / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 53.839914 KDa
Recombinant expressionOrganism: Escherichia coli BL21 (bacteria)
SequenceString: MQYKLALNGK TLKGETTTEA VDAATAEKVF KQYANDNGVD GEWTYDDATK TFTVTEHMHH HHHHSSGLEV LFQGPGSADA HGWHTLLRE WEPMLQDYLL SNRRQLEVTS LILKLQKCQE KVVEDGDYDT AETLRQRLEE LEQEKGRLSW ALPSQQPALR S FLGYLAAQ ...String:
MQYKLALNGK TLKGETTTEA VDAATAEKVF KQYANDNGVD GEWTYDDATK TFTVTEHMHH HHHHSSGLEV LFQGPGSADA HGWHTLLRE WEPMLQDYLL SNRRQLEVTS LILKLQKCQE KVVEDGDYDT AETLRQRLEE LEQEKGRLSW ALPSQQPALR S FLGYLAAQ IQVALHGATQ RAGSDDPEAP LEGQLRTTAQ DSLPASITRR DWLIREKQRL QKEIEALQAR MSALEAKEKR LS QELEEQE VLLRWPGCDL MALVAQMSPG QLQEVSKALG ETLTSANQAP FQVEPPETLR SLRERTKSLN LAVRELTAQV CSG EKLCSS LRRRLSDLDT RLPALLEAKM LALSGSCFST AKELTEEIWA LSSEREGLEM FLGRLLALSS RNSRRLGIVK EDHL RCRQD LALQDAAHKT RMKANTVKCM EVLEGQLSSC RCPLLGRVWK ADLETCQLLM QSLQLQEAGS SPHAEDEEQV HST

UniProtKB: Disrupted in schizophrenia 1 homolog

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration2.8 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
50.0 mMC4H11NO3Tris
300.0 mMNaClsodium chloride
5.0 mMC4H10O2S2DTT
0.4 %C32H58N2O7SCHAPS
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 90 sec. / Pretreatment - Atmosphere: AIR / Details: 15mA
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 294 K / Instrument: FEI VITROBOT MARK IV
DetailsMonodisperse

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number real images: 6039 / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.75 µm / Nominal defocus min: 1.25 µm / Nominal magnification: 81000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1439840
CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionNumber classes used: 2 / Applied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 227140
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final 3D classificationNumber classes: 5 / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

1-v4


Chain - Residue range: 322-722 / Chain - Source name: AlphaFold / Chain - Initial model type: in silico model
SoftwareName: UCSF ChimeraX
RefinementProtocol: FLEXIBLE FIT
Output model

PDB-9rux:
Cryo-EM structure of DISC1 core

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