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- PDB-9for: Structure of heteromeric amyloid filament of TDP-43 and AXNA11 fr... -

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Basic information

Entry
Database: PDB / ID: 9for
TitleStructure of heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP Type C (variant 1)
Components
  • Annexin A11
  • TAR DNA-binding protein 43
KeywordsPROTEIN 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 / 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 by host of viral transcription / phagocytosis / phagocytic vesicle / pre-mRNA intronic binding / response to endoplasmic reticulum stress / RNA splicing / negative regulation of protein phosphorylation / mRNA 3'-UTR binding / molecular condensate scaffold activity / regulation of circadian rhythm / regulation of protein stability / positive regulation of insulin secretion / positive regulation of protein import into nucleus / spindle / response to calcium ion / cytoplasmic stress granule / mRNA processing / calcium-dependent protein binding / rhythmic process / melanosome / MHC class II protein complex binding / nuclear envelope / double-stranded DNA binding / midbody / regulation of gene expression / 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
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)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.75 Å
AuthorsArseni, D. / Ryskeldi-Falcon, B.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom) United Kingdom
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.
#1: Journal: 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.
#2: 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
DepositionJun 12, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 24, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 16, 2024Group: Data collection / Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / em_admin / pdbx_entry_details
Item: _em_admin.last_update
Revision 1.2Oct 23, 2024Group: Data collection / Database references / Category: citation / citation_author / 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
o: TAR DNA-binding protein 43
p: Annexin A11
A: TAR DNA-binding protein 43
B: Annexin A11
C: TAR DNA-binding protein 43
D: Annexin A11
E: TAR DNA-binding protein 43
F: Annexin A11
G: TAR DNA-binding protein 43
H: Annexin A11


Theoretical massNumber of molelcules
Total (without water)49,16410
Polymers49,16410
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
TAR DNA-binding protein 43 / TDP-43


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
Annexin A11 / 56 kDa autoantigen / Annexin XI / Annexin-11 / Calcyclin-associated annexin 50 / CAP-50


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
Has protein modificationN

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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: Heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP Type C (variant 1)
Type: TISSUE / Entity ID: all / Source: NATURAL
Molecular weightValue: 9.8 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human) / Tissue: Brain
Buffer solutionpH: 7.4
SpecimenEmbedding 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)
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 38 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: RELION / Version: 5 / Category: 3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -1.83 ° / Axial rise/subunit: 4.98 Å / Axial symmetry: C1
3D reconstructionResolution: 2.75 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 18020 / Symmetry type: HELICAL
RefinementResolution: 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
RfactorNum. reflection% reflection
Rwork0.30999 --
obs0.30999 37909 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 55.771 Å2
Refinement stepCycle: 1 / Total: 689
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0090.011699
ELECTRON MICROSCOPYr_bond_other_d00.016619
ELECTRON MICROSCOPYr_angle_refined_deg2.1391.723934
ELECTRON MICROSCOPYr_angle_other_deg0.6061.6961409
ELECTRON MICROSCOPYr_dihedral_angle_1_deg8.606598
ELECTRON MICROSCOPYr_dihedral_angle_2_deg1.14651
ELECTRON MICROSCOPYr_dihedral_angle_3_deg13.1461098
ELECTRON MICROSCOPYr_dihedral_angle_4_deg
ELECTRON MICROSCOPYr_chiral_restr0.0870.287
ELECTRON MICROSCOPYr_gen_planes_refined0.0080.02908
ELECTRON MICROSCOPYr_gen_planes_other0.0010.02186
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it7.5535.101398
ELECTRON MICROSCOPYr_mcbond_other7.5485.098398
ELECTRON MICROSCOPYr_mcangle_it11.9919.176494
ELECTRON MICROSCOPYr_mcangle_other11.9899.18495
ELECTRON MICROSCOPYr_scbond_it9.2615.768301
ELECTRON MICROSCOPYr_scbond_other9.255.762301
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other13.9210.164441
ELECTRON MICROSCOPYr_long_range_B_refined19.65746.33627
ELECTRON MICROSCOPYr_long_range_B_other19.64346.48628
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 2.75→2.821 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork1.143 2823 -
obs--100 %

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