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

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Basic information

Entry
Database: PDB / ID: 9fof
TitleStructure of heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP Type C (variant 2)
Components
  • Annexin A11
  • TAR DNA-binding protein 43
KeywordsPROTEIN FIBRIL / TDP-43 / ANXA11 / amyloid / heteromeric amyloid / FTLD-TDP / neurodegeneration / dementia / brain / protein 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 / negative regulation of protein phosphorylation / molecular condensate scaffold activity / mRNA 3'-UTR binding / regulation of protein stability / regulation of circadian rhythm / positive regulation of insulin secretion / mRNA processing / positive regulation of protein import into nucleus / response to calcium ion / cytoplasmic stress granule / spindle / calcium-dependent protein binding / rhythmic process / melanosome / MHC class II protein complex binding / nuclear envelope / midbody / regulation of gene expression / double-stranded DNA binding / regulation of apoptotic process / collagen-containing extracellular matrix / 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 / mitochondrion / DNA binding / RNA binding / extracellular exosome / nucleoplasm / identical protein binding / membrane / nucleus / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Annexin A11 / : / TAR DNA-binding protein 43, C-terminal / TAR DNA-binding protein 43, N-terminal / TAR DNA-binding protein 43, N-terminal domain / Annexin repeat, conserved site / Annexin repeat signature. / Annexin / Annexin / Annexin repeats ...Annexin A11 / : / TAR DNA-binding protein 43, C-terminal / TAR DNA-binding protein 43, N-terminal / TAR DNA-binding protein 43, N-terminal domain / 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: 2.9 Å
AuthorsArseni, D. / Ryskeldi-Falcon, B.
Funding support United Kingdom, 1items
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, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 24, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
q: TAR DNA-binding protein 43
r: 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
I: TAR DNA-binding protein 43
J: Annexin A11


Theoretical massNumber of molelcules
Total (without water)60,22212
Polymers60,22212
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(0.997755, -0.06697), (0.06697, 0.997755), (1)8.85959, -8.28486, -9.92
3given(0.999439, -0.033504), (0.033504, 0.999439), (1)4.36038, -4.21666, -4.96
4given(0.999439, 0.033504), (-0.033504, 0.999439), (1)-4.21666, 4.36038, 4.96
5given(0.997755, 0.06697), (-0.06697, 0.997755), (1)-8.28486, 8.85959, 9.92
6given(0.994951, 0.100362), (-0.100362, 0.994951), (1)-12.20003, 13.49257, 14.88

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Components

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


Mass: 6231.870 Da / Num. of mol.: 6 / 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.: 6 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Tissue: Brain / References: UniProt: P50995

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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
Source (natural)Organism: Homo sapiens (human) / Tissue: Brain
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
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 BIOCONTINUUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -1.92 ° / Axial rise/subunit: 4.96 Å / Axial symmetry: C1
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 10842 / Symmetry type: HELICAL
RefinementResolution: 2.9→96 Å / Cor.coef. Fo:Fc: 0.702 / SU B: 1.687 / SU ML: 0.033 / ESU R: 0.281
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.68623 --
obs0.68623 37583 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 90.432 Å2
Refinement stepCycle: 1 / Total: 696
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0070.011707
ELECTRON MICROSCOPYr_bond_other_d0.0080.016625
ELECTRON MICROSCOPYr_angle_refined_deg1.4911.724945
ELECTRON MICROSCOPYr_angle_other_deg0.7131.6951422
ELECTRON MICROSCOPYr_dihedral_angle_1_deg7.832598
ELECTRON MICROSCOPYr_dihedral_angle_2_deg6.09551
ELECTRON MICROSCOPYr_dihedral_angle_3_deg12.4231099
ELECTRON MICROSCOPYr_dihedral_angle_4_deg
ELECTRON MICROSCOPYr_chiral_restr0.0770.288
ELECTRON MICROSCOPYr_gen_planes_refined0.0050.02915
ELECTRON MICROSCOPYr_gen_planes_other0.0020.02191
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_it3.4028.708398
ELECTRON MICROSCOPYr_mcbond_other3.388.706398
ELECTRON MICROSCOPYr_mcangle_it5.15513.073494
ELECTRON MICROSCOPYr_mcangle_other5.15813.082495
ELECTRON MICROSCOPYr_scbond_it5.19.456309
ELECTRON MICROSCOPYr_scbond_other5.0959.455309
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other8.19213.981452
ELECTRON MICROSCOPYr_long_range_B_refined11.275109.56639
ELECTRON MICROSCOPYr_long_range_B_other11.267109.55640
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 2.9→2.975 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.622 2764 -
obs--100 %

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