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- EMDB-75195: S305I Frontotemporal Lobar Degeneration (FTLD) type I tau filament -

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Basic information

Entry
Database: EMDB / ID: EMD-75195
TitleS305I Frontotemporal Lobar Degeneration (FTLD) type I tau filament
Map dataS305I Type I Fold Map
Sample
  • Tissue: Filaments purified S305I FTLD individual brain tissue
    • Protein or peptide: Microtubule-associated protein tau
Keywordstau / MAPT / FTD / FTLD / amyloid / neurodegeneration / PROTEIN FIBRIL
Function / homology
Function and homology information


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 ...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 microtubule-based movement / regulation of chromosome organization / intracellular distribution of mitochondria / central nervous system neuron development / 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 / Caspase-mediated cleavage of cytoskeletal proteins / regulation of microtubule polymerization or depolymerization / negative regulation of mitochondrial fission / glial cell projection / neurofibrillary tangle assembly / positive regulation of axon extension / regulation of cellular response to heat / Activation of AMPK downstream of NMDARs / positive regulation of superoxide anion generation / positive regulation of protein localization / regulation of long-term synaptic depression / cellular response to brain-derived neurotrophic factor stimulus / supramolecular fiber organization / positive regulation of microtubule polymerization / cytoplasmic microtubule organization / somatodendritic compartment / synapse assembly / regulation of calcium-mediated signaling / axon cytoplasm / astrocyte activation / phosphatidylinositol binding / nuclear periphery / enzyme inhibitor activity / stress granule assembly / protein phosphatase 2A binding / regulation of microtubule cytoskeleton organization / regulation of autophagy / cellular response to reactive oxygen species / Hsp90 protein binding / microglial cell activation / cellular response to nerve growth factor stimulus / protein homooligomerization / synapse organization / PKR-mediated signaling / regulation of synaptic plasticity / response to lead ion / SH3 domain binding / microtubule cytoskeleton organization / memory / neuron projection development / cytoplasmic ribonucleoprotein granule / 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 / microtubule binding / sequence-specific DNA binding / protein-macromolecule adaptor activity / amyloid fibril formation / dendritic spine / microtubule / learning or memory / neuron projection / membrane raft / negative regulation of gene expression / axon / neuronal cell body / DNA damage response / dendrite / protein kinase binding / enzyme binding / mitochondrion / DNA binding / RNA binding / extracellular region / identical protein binding / nucleus
Similarity search - Function
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. / :
Similarity search - Domain/homology
Microtubule-associated protein tau
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsPan HS / Merz GE / Tse E / Southworth DR
Funding support United States, 13 items
OrganizationGrant numberCountry
Other privateA2023019F
National Institutes of Health/National Institute on Aging (NIH/NIA)P30AG062422 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)P01AG019724 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)U01AG057195 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)U19AG063911 United States
Other private
Other private
National Institutes of Health/National Institute on Aging (NIH/NIA)U19: AG063911 United States
Other privateU54 NS092089
Other privateU01 AG045390
National Institutes of Health/National Institute on Aging (NIH/NIA)P01 AG019724 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)P30 AG062422 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)U24 AG21886) United States
CitationJournal: bioRxiv / Year: 2026
Title: Distinct tau filament folds in familial frontotemporal dementia due to the S305I mutation.
Authors: Henry S Pan / Gregory E Merz / Alissa Nana Li / Minh Quan Le / Hyunil Jo / Athena Quddus / Anthony Yung / Rian C Kormos / Arthur A Melo / Eliana Marisa Ramos / Argentina Lario Lago / ...Authors: Henry S Pan / Gregory E Merz / Alissa Nana Li / Minh Quan Le / Hyunil Jo / Athena Quddus / Anthony Yung / Rian C Kormos / Arthur A Melo / Eliana Marisa Ramos / Argentina Lario Lago / Salvatore Spina / Lea T Grinberg / Howard J Rosen / Eric Tse / Maria Luisa Gorno-Tempini / William F DeGrado / William W Seeley / Daniel R Southworth
Abstract: Frontotemporal lobar degeneration with tau inclusions (FTLD-tau) comprise a class of fatal heterogeneous neurodegenerative diseases. Approximately 10% arise from pathogenic MAPT mutations and often ...Frontotemporal lobar degeneration with tau inclusions (FTLD-tau) comprise a class of fatal heterogeneous neurodegenerative diseases. Approximately 10% arise from pathogenic MAPT mutations and often cause severe, early-onset disease with pathology that is distinct yet partially overlapping with sporadic cases. Here, we evaluated post-mortem tissue from a patient with FTLD-tau due to S305I showing neuropathology most consistent with argyrophilic grain disease (AGD), a prevalent limbic tauopathy of aging. Structures determined by cryo-electron microscopy reveal tau filament folds that differ from those found in sporadic AGD or other tauopathies and feature a 4-layer architecture stabilized by the Ile substitution within its core. Comparative structural analysis reveals conserved motifs are shared among AGD, corticobasal degeneration, and P301T. A well-defined density stacks along a cationic cleft, indicative of a bound RNA-like polyanion or small-molecule. analysis shows the S305I mutation promotes fibrilization relative to normal tau. These results demonstrate that stabilizes a distinct aggregation-prone tau fold that likely contributes to disease pathology and heterogeneity beyond its known splicing defects, and underscore potential limitations of using the most pathologically similar genetic form as a model for sporadic FTLD-tau.
History
DepositionJan 21, 2026-
Header (metadata) releaseMar 11, 2026-
Map releaseMar 11, 2026-
UpdateMar 11, 2026-
Current statusMar 11, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_75195.png

Downloads & links

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Map

FileDownload / File: emd_75195.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationS305I Type I Fold Map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 300 pix.
= 250.2 Å		0.83 Å/pix.
x 300 pix.
= 250.2 Å		0.83 Å/pix.
x 300 pix.
= 250.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.834 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.00897
Minimum - Maximum-0.03406061 - 0.06842402
Average (Standard dev.)0.000060769602 (±0.0013636505)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 250.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_75195_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: S305I Type I Fold Half-map 1 from the 3D Refinement

Fileemd_75195_half_map_1.map
AnnotationS305I Type I Fold Half-map 1 from the 3D Refinement
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: S305I Type I Fold Half-map 2 from the 3D Refinement

Fileemd_75195_half_map_2.map
AnnotationS305I Type I Fold Half-map 2 from the 3D Refinement
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Filaments purified S305I FTLD individual brain tissue

EntireName: Filaments purified S305I FTLD individual brain tissue
Components
  • Tissue: Filaments purified S305I FTLD individual brain tissue
    • Protein or peptide: Microtubule-associated protein tau

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Supramolecule #1: Filaments purified S305I FTLD individual brain tissue

SupramoleculeName: Filaments purified S305I FTLD individual brain tissue / type: tissue / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Microtubule-associated protein tau

MacromoleculeName: Microtubule-associated protein tau / type: protein_or_peptide / ID: 1 / Number of copies: 11 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.562394 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
GKVQIINKKL DLSNVQSKCG SKDNIKHVPG GGIVQIVYKP VDLSKVTSKC GSLGNIHHKP GGGQVEVKSE KLDFKDRVQS KIGSLDNIT HVPGGGNKKI ETHKLTFR

UniProtKB: Microtubule-associated protein tau

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statetissue

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Sample preparation

BufferpH: 7.4
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY / Support film - Film thickness: 12
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 7393 / Average exposure time: 5.4 sec. / Average electron dose: 46.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Calibrated magnification: 105000 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 4.78 Å
Applied symmetry - Helical parameters - Δ&Phi: 178.6 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 5.0.0) / Number images used: 47171
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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