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Entry
Database: EMDB / ID: EMD-51358
TitleStructure of heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP Type C individual 2 (variant 1)
Map dataStructure of heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP Type C individual 2
Sample
  • Tissue: Structure of heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP Type C individual 2 (variant 1)
Keywordsheteromeric amyloid filament / PROTEIN FIBRIL
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsArseni D
Funding support United Kingdom, 1 items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom) United Kingdom
CitationJournal: Nature / Year: 2024
Title: Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP type C.
Authors: Diana Arseni / Takashi Nonaka / Max H Jacobsen / Alexey G Murzin / Laura Cracco / Sew Y Peak-Chew / Holly J Garringer / Ito Kawakami / Hisaomi Suzuki / Misumoto Onaya / Yuko Saito / Shigeo ...Authors: Diana Arseni / Takashi Nonaka / Max H Jacobsen / Alexey G Murzin / Laura Cracco / Sew Y Peak-Chew / Holly J Garringer / Ito Kawakami / Hisaomi Suzuki / Misumoto Onaya / Yuko Saito / Shigeo Murayama / Changiz Geula / Ruben Vidal / Kathy L Newell / Marsel Mesulam / Bernardino Ghetti / Masato Hasegawa / Benjamin Ryskeldi-Falcon /
Abstract: Neurodegenerative diseases are characterized by the abnormal filamentous assembly of specific proteins in the central nervous system. Human genetic studies have established a causal role for protein ...Neurodegenerative diseases are characterized by the abnormal filamentous assembly of specific proteins in the central nervous system. Human genetic studies have established a causal role for protein assembly in neurodegeneration. However, the underlying molecular mechanisms remain largely unknown, which is limiting progress in developing clinical tools for these diseases. Recent advances in cryo-electron microscopy have enabled the structures of the protein filaments to be determined from the brains of patients. All neurodegenerative diseases studied to date have been characterized by the self-assembly of proteins in homomeric amyloid filaments, including that of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) types A and B. Here we used cryo-electron microscopy to determine filament structures from the brains of individuals with FTLD-TDP type C, one of the most common forms of sporadic FTLD-TDP. Unexpectedly, the structures revealed that a second protein, annexin A11 (ANXA11), co-assembles with TDP-43 in heteromeric amyloid filaments. The ordered filament fold is formed by TDP-43 residues G282/G284-N345 and ANXA11 residues L39-Y74 from their respective low-complexity domains. Regions of TDP-43 and ANXA11  that were previously implicated in protein-protein interactions form an extensive hydrophobic interface at the centre of the filament fold. Immunoblots of the filaments revealed that the majority of ANXA11 exists as an approximately 22 kDa N-terminal fragment lacking the annexin core domain. Immunohistochemistry of brain sections showed the colocalization of ANXA11 and TDP-43 in inclusions, redefining the histopathology of FTLD-TDP type C. This work establishes a central role for ANXA11 in FTLD-TDP type C. The unprecedented formation of heteromeric amyloid filaments in the human brain revises our understanding of amyloid assembly and may be of significance for the pathogenesis of neurodegenerative diseases.
History
DepositionAug 15, 2024-
Header (metadata) releaseAug 27, 2025-
Map releaseAug 27, 2025-
UpdateMar 18, 2026-
Current statusMar 18, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_51358.png

Downloads & links

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Map

FileDownload / File: emd_51358.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationStructure of heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP Type C individual 2
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 256 pix.
= 212.48 Å		0.83 Å/pix.
x 256 pix.
= 212.48 Å		0.83 Å/pix.
x 256 pix.
= 212.48 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0122
Minimum - Maximum-0.023210201 - 0.04666105
Average (Standard dev.)0.00031130787 (±0.002812644)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 212.48 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Structure of heteromeric amyloid filament of TDP-43 and...

Fileemd_51358_half_map_1.map
AnnotationStructure of heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP Type C individual 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Structure of heteromeric amyloid filament of TDP-43 and...

Fileemd_51358_half_map_2.map
AnnotationStructure of heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP Type C individual 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Structure of heteromeric amyloid filament of TDP-43 and AXNA11 fr...

EntireName: Structure of heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP Type C individual 2 (variant 1)
Components
  • Tissue: Structure of heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP Type C individual 2 (variant 1)

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Supramolecule #1: Structure of heteromeric amyloid filament of TDP-43 and AXNA11 fr...

SupramoleculeName: Structure of heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP Type C individual 2 (variant 1)
type: tissue / ID: 1 / Parent: 0
Source (natural)Organism: Homo sapiens (human)

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 38.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 4.81 Å
Applied symmetry - Helical parameters - Δ&Phi: -1.82 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 5) / Number images used: 8236
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final angle assignmentType: NOT APPLICABLE

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