EMDB-48555: Structure of D421-Truncated Tau Fibril

Basic information

Entry

Database: EMDB / ID: EMD-48555

• Title: Structure of D421-Truncated Tau Fibril

Sample

• Cell: Tau 0N (1-421)
  • Protein or peptide: Microtubule-associated protein tau

• Keywords: Tau / amyloid fibrils / STRUCTURAL PROTEIN

Function / homology

Function:

plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / negative regulation of protein localization to mitochondrion / neurofibrillary tangle / microtubule lateral binding / axonal transport / tubulin complex / positive regulation of protein localization to synapse / phosphatidylinositol bisphosphate binding / generation of neurons / rRNA metabolic process / axonal transport of mitochondrion / regulation of mitochondrial fission / axon development / regulation of chromosome organization / regulation of microtubule-based movement / central nervous system neuron development / intracellular distribution of mitochondria / minor groove of adenine-thymine-rich DNA binding / lipoprotein particle binding / microtubule polymerization / negative regulation of mitochondrial membrane potential / regulation of microtubule polymerization / dynactin binding / apolipoprotein binding / main axon / protein polymerization / axolemma / glial cell projection / Caspase-mediated cleavage of cytoskeletal proteins / regulation of microtubule polymerization or depolymerization / negative regulation of mitochondrial fission / neurofibrillary tangle assembly / positive regulation of axon extension / regulation of cellular response to heat / synapse assembly / Activation of AMPK downstream of NMDARs / regulation of long-term synaptic depression / positive regulation of superoxide anion generation / positive regulation of protein localization / cellular response to brain-derived neurotrophic factor stimulus / supramolecular fiber organization / cytoplasmic microtubule organization / regulation of calcium-mediated signaling / somatodendritic compartment / axon cytoplasm / positive regulation of microtubule polymerization / astrocyte activation / phosphatidylinositol binding / enzyme inhibitor activity / nuclear periphery / stress granule assembly / protein phosphatase 2A binding / regulation of microtubule cytoskeleton organization / cellular response to reactive oxygen species / Hsp90 protein binding / microglial cell activation / cellular response to nerve growth factor stimulus / synapse organization / PKR-mediated signaling / regulation of synaptic plasticity / protein homooligomerization / response to lead ion / SH3 domain binding / microtubule cytoskeleton organization / memory / regulation of autophagy / cytoplasmic ribonucleoprotein granule / neuron projection development / cell-cell signaling / single-stranded DNA binding / protein-folding chaperone binding / cellular response to heat / microtubule cytoskeleton / growth cone / actin binding / cell body / double-stranded DNA binding / protein-macromolecule adaptor activity / microtubule binding / sequence-specific DNA binding / dendritic spine / amyloid fibril formation / microtubule / learning or memory / neuron projection / membrane raft / axon / negative regulation of gene expression / neuronal cell body / DNA damage response / dendrite / protein kinase binding / enzyme binding / mitochondrion / DNA binding / RNA binding / extracellular region / identical protein binding / nucleus

Domain/homology:

Microtubule-associated protein Tau / Microtubule associated protein, tubulin-binding repeat / Tau and MAP protein, tubulin-binding repeat / Tau and MAP proteins tubulin-binding repeat signature. / Tau and MAP proteins tubulin-binding repeat profile. / :

Component:

Microtubule-associated protein tau

• Biological species: Escherichia coli (E. coli) / Homo sapiens (human)
• Method: helical reconstruction / cryo EM / Resolution: 2.9 Å
• Authors: El Mammeri N / Duan P / Hong M

Funding support

United States, 1 items

Organization	Grant number	Country
National Institutes of Health/National Institute on Aging (NIH/NIA)	AG059661	United States

• Citation: Journal: J Mol Biol / Year: 2025; Title: Structures of ΔD421 Truncated Tau Fibrils.; Authors: Nadia El Mammeri / Pu Duan / Mei Hong / ; Abstract: The microtubule-associated protein tau aggregates into pathological β-sheet amyloid fibrils in Alzheimer's disease (AD) and other neurodegenerative diseases. In these aggregates, tau is chemically modified, including abnormal hyperphosphorylation and truncation. Truncation after D421 in the C-terminal domain occurs at early stages of AD. Here we investigate the structures of ΔD421-truncated 0N4R tau fibrils assembled in vitro in the absence of anionic cofactors. Using solid-state NMR spectroscopy and cryoelectron microscopy, we show that ΔD421-truncated 0N4R tau forms homogeneous fibrils whose rigid core adopts a three-layered β-sheet structure that spans R2, R3 and R4 repeats. This structure is essentially identical to that of full-length tau containing phospho-mimetic mutations at the PHF1 epitope in the C-terminal domain. In comparison, a ΔD421-truncated tau that additionally contains three phospho-mimetic mutations at the AT8 epitope in the proline-rich region forms a fibril core that includes the first half of the C-terminal domain, which is excluded from all known pathological tau fibril cores. These results indicate that the posttranslational modification code of tau contains redundancy: both charge modification and truncation of the C-terminal domain promote a three-layered β-sheet structure, which resembles pathological four-repeat tau structures in several tauopathies. In comparison, reducing the positive charges at the AT8 epitope in ΔD421-truncated tau promotes a fibril core that includes an immobilized C-terminal domain. The absence of this structure in tauopathy brains implies that ΔD421 truncation does not occur in conjunction with AT8 phosphorylation in diseased brains.

History

Deposition	Jan 7, 2025	-
Header (metadata) release	Mar 12, 2025	-
Map release	Mar 12, 2025	-
Update	Mar 19, 2025	-
Current status	Mar 19, 2025	Processing site: RCSB / Status: Released

Map

• File: Download / File: emd_48555.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
• Voxel size: X=Y=Z: 1.06 Å

Density

Contour Level	By AUTHOR: 0.008
Minimum - Maximum	-0.037562523 - 0.079330236
Average (Standard dev.)	0.000060623825 (±0.002485127)

• Symmetry: Space group: 1

Details

EMDB XML:

Map geometry	Axis order X Y Z Origin 0 0 0 Dimensions 384 384 384 Spacing 384 384 384
Cell	A=B=C: 407.03998 Å α=β=γ: 90.0 °

Supplemental data

Mask #1

• File: emd_48555_msk_1.map

Additional map: #1

• File: emd_48555_additional_1.map

Half map: #2

• File: emd_48555_half_map_1.map

Half map: #1

• File: emd_48555_half_map_2.map

Sample components

Entire : Tau 0N (1-421)

• Entire: Name: Tau 0N (1-421)

Components

• Cell: Tau 0N (1-421)
  • Protein or peptide: Microtubule-associated protein tau

Supramolecule #1: Tau 0N (1-421)

• Supramolecule: Name: Tau 0N (1-421) / type: cell / ID: 1 / Parent: 0 / Macromolecule list: all / Details: tau construct with truncation at D421
• Source (natural): Organism: Escherichia coli (E. coli)

Macromolecule #1: Microtubule-associated protein tau

• Macromolecule: Name: Microtubule-associated protein tau / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
• Source (natural): Organism: Homo sapiens (human)
• Molecular weight: Theoretical: 9.667116 KDa
• Recombinant expression: Organism: Escherichia coli (E. coli)

Sequence

String:

GKVQIINKKL DLSNVQSKCG SKDNIKHVPG GGSVQIVYKP VDLSKVTSKC GSLGNIHHKP GGGQVEVKSE KLDFKDRVQS KIGSLDNIT H

UniProtKB: Microtubule-associated protein tau

Experimental details

Structure determination

• Method: cryo EM
• Processing: helical reconstruction
• Aggregation state: filament

Sample preparation

• Buffer: pH: 7.5
• Vitrification: Cryogen name: ETHANE / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK IV

Electron microscopy

• Microscope: TFS KRIOS
• Image recording: Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 1.04756 e/Ų
• Electron beam: Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
• Electron optics: Illumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.2 µm
• Experimental equipment: Model: Titan Krios / Image courtesy: FEI Company

Image processing

• Final reconstruction: Applied symmetry - Helical parameters - Δz: 4.768 Å; Applied symmetry - Helical parameters - Δ&Phi: -0.93 °; 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: 31533
• Startup model: Type of model: NONE
• Final angle assignment: Type: NOT APPLICABLE

Atomic model buiding 1

• Refinement: Protocol: AB INITIO MODEL

Output model

PDB-9mr8:
Structure of D421-Truncated Tau Fibril