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- EMDB-50621: Structure of heteromeric amyloid filament of TDP-43 and AXNA11 fr... -

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Entry
Database: EMDB / ID: EMD-50621
TitleStructure of heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP Type C (variant 2)
Map dataTDP-43/ANXA11 FTLD-TDP type C heteroamyloid filament variant 2 map
Sample
  • Tissue: heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP Type C (variant 1)
    • Protein or peptide: TAR DNA-binding protein 43
    • Protein or peptide: Annexin A11
KeywordsTDP-43 / ANXA11 / amyloid / heteromeric amyloid / FTLD-TDP / neurodegeneration / dementia / brain / protein filament / PROTEIN FIBRIL
Function / homology
Function and homology information


cytokinetic process / nuclear inner membrane organization / interchromatin granule / perichromatin fibrils / 3'-UTR-mediated mRNA destabilization / specific granule / calcium-dependent phospholipid binding / phosphatidylethanolamine binding / S100 protein binding / vesicle membrane ...cytokinetic process / nuclear inner membrane organization / interchromatin granule / perichromatin fibrils / 3'-UTR-mediated mRNA destabilization / specific granule / calcium-dependent phospholipid binding / phosphatidylethanolamine binding / S100 protein binding / vesicle membrane / azurophil granule / 3'-UTR-mediated mRNA stabilization / intracellular membraneless organelle / phosphatidylserine binding / negative regulation of protein phosphorylation / host-mediated suppression of viral transcription / phagocytosis / pre-mRNA intronic binding / phagocytic vesicle / RNA splicing / response to endoplasmic reticulum stress / mRNA 3'-UTR binding / molecular condensate scaffold activity / regulation of circadian rhythm / response to calcium ion / positive regulation of insulin secretion / regulation of protein stability / positive regulation of protein import into nucleus / spindle / mRNA processing / cytoplasmic stress granule / calcium-dependent protein binding / MHC class II protein complex binding / rhythmic process / melanosome / nuclear envelope / : / regulation of gene expression / double-stranded DNA binding / midbody / regulation of apoptotic process / amyloid fibril formation / regulation of cell cycle / nuclear speck / RNA polymerase II cis-regulatory region sequence-specific DNA binding / negative regulation of gene expression / intracellular membrane-bounded organelle / calcium ion binding / lipid binding / chromatin / mitochondrion / DNA binding / RNA binding / extracellular exosome / nucleoplasm / identical protein binding / nucleus / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Annexin A11 / TAR DNA-binding protein 43, N-terminal / : / TAR DNA-binding protein 43, N-terminal domain / TAR DNA-binding protein 43, C-terminal / Annexin repeat, conserved site / Annexin repeat signature. / Annexin / Annexin / Annexin repeats ...Annexin A11 / TAR DNA-binding protein 43, N-terminal / : / TAR DNA-binding protein 43, N-terminal domain / TAR DNA-binding protein 43, C-terminal / Annexin repeat, conserved site / Annexin repeat signature. / Annexin / Annexin / Annexin repeats / Annexin repeat / Annexin superfamily / Annexin repeat profile. / RNA recognition motif / RNA recognition motif / Eukaryotic RNA Recognition Motif (RRM) profile. / RNA recognition motif domain / RNA-binding domain superfamily / Nucleotide-binding alpha-beta plait domain superfamily
Similarity search - Domain/homology
Annexin A11 / TAR DNA-binding protein 43
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsArseni D / Ryskeldi-Falcon B
Funding support United Kingdom, 1 items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom) United Kingdom
CitationJournal: bioRxiv / 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 characterised by the abnormal filamentous assembly of specific proteins in the central nervous system . Human genetic studies established a causal role for protein ...Neurodegenerative diseases are characterised by the abnormal filamentous assembly of specific proteins in the central nervous system . Human genetic studies 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 electron cryo-microscopy (cryo-EM) have enabled the structures of the protein filaments to be determined from patient brains . All diseases studied to date have been characterised by the self-assembly of a single intracellular protein 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-EM 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 G282/284-N345 and ANXA11 residues L39-L74 from their respective low-complexity domains (LCDs). Regions of TDP-43 and ANXA11 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 a ∼22 kDa N-terminal fragment (NTF) lacking the annexin core domain. Immunohistochemistry of brain sections confirmed the co-localisation 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 human brain revises our understanding of amyloid assembly and may be of significance for the pathogenesis of neurodegenerative diseases.
History
DepositionJun 11, 2024-
Header (metadata) releaseJul 24, 2024-
Map releaseJul 24, 2024-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_50621.png

Downloads & links

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Map

FileDownload / File: emd_50621.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationTDP-43/ANXA11 FTLD-TDP type C heteroamyloid filament variant 2 map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 256 pix.
= 220.16 Å		0.86 Å/pix.
x 256 pix.
= 220.16 Å		0.86 Å/pix.
x 256 pix.
= 220.16 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.86 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0158
Minimum - Maximum-0.04374611 - 0.07104856
Average (Standard dev.)0.00016519589 (±0.0044539846)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 220.16 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_50621_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: TDP-43/ANXA11 FTLD-TDP type C heteroamyloid filament variant 2 half 1

Fileemd_50621_half_map_1.map
AnnotationTDP-43/ANXA11 FTLD-TDP type C heteroamyloid filament variant 2 half 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: TDP-43/ANXA11 FTLD-TDP type C heteroamyloid filament variant 2 half 2

Fileemd_50621_half_map_2.map
AnnotationTDP-43/ANXA11 FTLD-TDP type C heteroamyloid filament variant 2 half 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 : heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP T...

EntireName: heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP Type C (variant 1)
Components
  • Tissue: heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP Type C (variant 1)
    • Protein or peptide: TAR DNA-binding protein 43
    • Protein or peptide: Annexin A11

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Supramolecule #1: heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP T...

SupramoleculeName: heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP Type C (variant 1)
type: tissue / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human) / Tissue: Brain

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Macromolecule #1: TAR DNA-binding protein 43

MacromoleculeName: TAR DNA-binding protein 43 / type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human) / Tissue: Brain
Molecular weightTheoretical: 6.23187 KDa
SequenceString:
GFGNQGGFGN SRGGGAGLGN NQGSNMGGGM NFGAFSINPA MMAAAQAALQ SSWGMMGMLA SQQN

UniProtKB: TAR DNA-binding protein 43

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Macromolecule #2: Annexin A11

MacromoleculeName: Annexin A11 / type: protein_or_peptide / ID: 2 / Number of copies: 6 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human) / Tissue: Brain
Molecular weightTheoretical: 3.805148 KDa
SequenceString:
LDNVATYAGQ FNQDYLSGMA ANMSGTFGGA NMPNLY

UniProtKB: Annexin A11

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOCONTINUUM (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: 4.96 Å
Applied symmetry - Helical parameters - Δ&Phi: -1.92 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 10842
Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE

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