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Yorodumi- PDB-9for: Structure of heteromeric amyloid filament of TDP-43 and AXNA11 fr... -
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-Basic information
Entry | Database: PDB / ID: 9for | ||||||
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Title | Structure of heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP Type C (variant 1) | ||||||
Components |
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Keywords | PROTEIN FIBRIL / TDP-43 / ANXA11 / amyloid / heteromeric amyloid / FTLD-TDP / FTLD-TDP Type C / neurodegeneration / neurodegenerative disease / dementia / brain / filament | ||||||
Function / homology | Function and homology information cytokinetic process / nuclear inner membrane organization / interchromatin granule / perichromatin fibrils / 3'-UTR-mediated mRNA destabilization / specific granule / phosphatidylethanolamine binding / calcium-dependent phospholipid binding / S100 protein binding / azurophil granule ...cytokinetic process / nuclear inner membrane organization / interchromatin granule / perichromatin fibrils / 3'-UTR-mediated mRNA destabilization / specific granule / phosphatidylethanolamine binding / calcium-dependent phospholipid binding / S100 protein binding / azurophil granule / 3'-UTR-mediated mRNA stabilization / intracellular non-membrane-bounded organelle / phosphatidylserine binding / negative regulation by host of viral transcription / phagocytosis / pre-mRNA intronic binding / phagocytic vesicle / response to endoplasmic reticulum stress / RNA splicing / molecular condensate scaffold activity / negative regulation of protein phosphorylation / mRNA 3'-UTR binding / regulation of protein stability / positive regulation of insulin secretion / regulation of circadian rhythm / spindle / cytoplasmic stress granule / positive regulation of protein import into nucleus / response to calcium ion / mRNA processing / calcium-dependent protein binding / melanosome / rhythmic process / MHC class II protein complex binding / nuclear envelope / midbody / regulation of gene expression / double-stranded DNA binding / collagen-containing extracellular matrix / 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 / lipid binding / calcium ion binding / chromatin / mitochondrion / DNA binding / RNA binding / extracellular exosome / nucleoplasm / identical protein binding / membrane / nucleus / plasma membrane / cytosol / cytoplasm Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.75 Å | ||||||
Authors | Arseni, D. / Ryskeldi-Falcon, B. | ||||||
Funding support | United Kingdom, 1items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
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PDBx/mmCIF format | 9for.cif.gz | 93.5 KB | Display | PDBx/mmCIF format |
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PDB format | pdb9for.ent.gz | 71.2 KB | Display | PDB format |
PDBx/mmJSON format | 9for.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/fo/9for ftp://data.pdbj.org/pub/pdb/validation_reports/fo/9for | HTTPS FTP |
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-Related structure data
Related structure data | 50628MC 9fofC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 6027.645 Da / Num. of mol.: 5 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Tissue: Brain / References: UniProt: Q13148 #2: Protein/peptide | Mass: 3805.148 Da / Num. of mol.: 5 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Tissue: Brain / References: UniProt: P50995 |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: FILAMENT / 3D reconstruction method: helical reconstruction |
-Sample preparation
Component | Name: Heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP Type C (variant 1) Type: TISSUE / Entity ID: all / Source: NATURAL |
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Molecular weight | Value: 9.8 kDa/nm / Experimental value: NO |
Source (natural) | Organism: Homo sapiens (human) / Tissue: Brain |
Buffer solution | pH: 7.4 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES Details: Heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP Type C (variant 1) |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: TFS KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 1000 nm |
Image recording | Electron dose: 38 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
-Processing
EM software | Name: RELION / Version: 5 / Category: 3D reconstruction | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Helical symmerty | Angular rotation/subunit: -1.83 ° / Axial rise/subunit: 4.98 Å / Axial symmetry: C1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 2.75 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 18020 / Symmetry type: HELICAL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement | Resolution: 2.75→96.32 Å / Cor.coef. Fo:Fc: 0.819 / SU B: 6.419 / SU ML: 0.128 / ESU R: 0.119 Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
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Solvent computation | Solvent model: PARAMETERS FOR MASK CACLULATION | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 55.771 Å2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: 1 / Total: 689 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refine LS restraints |
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