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- EMDB-44133: filament of type 1 KD-mxyl miniature tau macrocycle derived from ... -

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Basic information

Entry
Database: EMDB / ID: EMD-44133
Titlefilament of type 1 KD-mxyl miniature tau macrocycle derived from 4R tauopathic fold
Map datafilament of type 1 KD-mxyl miniature tau macrocycle derived from 4R tauopathic fold
Sample
  • Cell: type 1 KD-mxyl miniature tau macrocycle derived from 4R tauopathic fold
    • Protein or peptide: Microtubule-associated protein tau
    • Protein or peptide: SER-VAL-GLN-ILE-VAL-TYR-LYS
  • Ligand: AMINO GROUP
  • Ligand: 1,3-dimethylbenzene
Keywordstauopathies / neurodegenerative disorders / seed-competent miniature tau macrocycle / PROTEIN FIBRIL
Function / homology
Function and homology information


plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / microtubule lateral binding / axonal transport / tubulin complex / positive regulation of protein localization to synapse / negative regulation of tubulin deacetylation / phosphatidylinositol bisphosphate binding ...plus-end-directed organelle transport along microtubule / histone-dependent DNA binding / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / microtubule lateral binding / axonal transport / tubulin complex / positive regulation of protein localization to synapse / negative regulation of tubulin deacetylation / phosphatidylinositol bisphosphate binding / generation of neurons / rRNA metabolic process / axonal transport of mitochondrion / regulation of mitochondrial fission / axon development / regulation of chromosome organization / 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 / dynactin binding / regulation of microtubule polymerization / 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 / Activation of AMPK downstream of NMDARs / synapse assembly / positive regulation of superoxide anion generation / regulation of long-term synaptic depression / positive regulation of protein localization / cellular response to brain-derived neurotrophic factor stimulus / supramolecular fiber organization / cytoplasmic microtubule organization / regulation of calcium-mediated signaling / positive regulation of microtubule polymerization / somatodendritic compartment / axon cytoplasm / astrocyte activation / stress granule assembly / phosphatidylinositol binding / nuclear periphery / regulation of microtubule cytoskeleton organization / protein phosphatase 2A binding / cellular response to reactive oxygen species / Hsp90 protein binding / microglial cell activation / cellular response to nerve growth factor stimulus / protein homooligomerization / synapse organization / regulation of synaptic plasticity / PKR-mediated signaling / response to lead ion / SH3 domain binding / microtubule cytoskeleton organization / memory / cytoplasmic ribonucleoprotein granule / neuron projection development / cell-cell signaling / single-stranded DNA binding / protein-folding chaperone binding / cellular response to heat / microtubule cytoskeleton / cell body / growth cone / actin binding / double-stranded DNA binding / protein-macromolecule adaptor activity / microtubule binding / dendritic spine / sequence-specific DNA binding / amyloid fibril formation / microtubule / learning or memory / neuron projection / regulation of autophagy / 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 / plasma membrane
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: 3.2 Å
AuthorsXu X / Angera JI / Rajewski HB / Jiang W / Del Valle RJ
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)R01AG074570 United States
National Science Foundation (NSF, United States)CHE2109008 United States
CitationJournal: Nat Chem / Year: 2025
Title: Macrocyclic β-arch peptides that mimic the structure and function of disease-associated tau folds.
Authors: Isaac J Angera / Xueyong Xu / Benjamin H Rajewski / Grace I Hallinan / Xiaoqi Zhang / Bernardino Ghetti / Ruben Vidal / Wen Jiang / Juan R Del Valle /
Abstract: Tauopathies are a class of neurodegenerative disorders that feature tau protein aggregates in the brain. Misfolded tau has the capacity to seed the fibrillization of soluble tau, leading to the prion- ...Tauopathies are a class of neurodegenerative disorders that feature tau protein aggregates in the brain. Misfolded tau has the capacity to seed the fibrillization of soluble tau, leading to the prion-like spread of aggregates. Within these filaments, tau protomers always exhibit a cross-β amyloid structure. However, distinct cross-β amyloid folds correlate with specific diseases. An understanding of how these conformations impact seeding activity remains elusive. Identifying the minimal epitopes required for transcellular propagation of tau aggregates represents a key step towards more relevant models of disease progression. Here we implement a diversity-oriented peptide macrocyclization approach towards miniature tau, or 'mini-tau', proteomimetics that can seed the aggregation of tau in engineered cells and primary neurons. Structural elucidation of one such seed-competent macrocycle reveals remarkable conformational congruence with core folds from patient-derived extracts of tau. The ability to impart β-arch form and function through peptide stapling has broad-ranging implications for the minimization and mimicry of pathological tau and other amyloid proteins that drive neurodegeneration.
History
DepositionMar 18, 2024-
Header (metadata) releaseMar 26, 2025-
Map releaseMar 26, 2025-
UpdateOct 8, 2025-
Current statusOct 8, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_44133.png

Downloads & links

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Map

FileDownload / File: emd_44133.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationfilament of type 1 KD-mxyl miniature tau macrocycle derived from 4R tauopathic fold
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 320 pix.
= 263.04 Å		0.82 Å/pix.
x 320 pix.
= 263.04 Å		0.82 Å/pix.
x 320 pix.
= 263.04 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.822 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.007
Minimum - Maximum-0.02594728 - 0.055066675
Average (Standard dev.)0.0000535047 (±0.0016750505)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 263.04 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map A

Fileemd_44133_half_map_1.map
AnnotationHalf Map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map B

Fileemd_44133_half_map_2.map
AnnotationHalf Map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : type 1 KD-mxyl miniature tau macrocycle derived from 4R tauopathi...

EntireName: type 1 KD-mxyl miniature tau macrocycle derived from 4R tauopathic fold
Components
  • Cell: type 1 KD-mxyl miniature tau macrocycle derived from 4R tauopathic fold
    • Protein or peptide: Microtubule-associated protein tau
    • Protein or peptide: SER-VAL-GLN-ILE-VAL-TYR-LYS
  • Ligand: AMINO GROUP
  • Ligand: 1,3-dimethylbenzene

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Supramolecule #1: type 1 KD-mxyl miniature tau macrocycle derived from 4R tauopathi...

SupramoleculeName: type 1 KD-mxyl miniature tau macrocycle derived from 4R tauopathic fold
type: cell / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
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: 15 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 2.24264 KDa
SequenceString:
(ACE)CDNIKHVPG GGSVQIVYKP VC

UniProtKB: Microtubule-associated protein tau

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Macromolecule #2: SER-VAL-GLN-ILE-VAL-TYR-LYS

MacromoleculeName: SER-VAL-GLN-ILE-VAL-TYR-LYS / type: protein_or_peptide / ID: 2 / Number of copies: 15 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 836.995 Da
SequenceString:
SVQIVYK

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Macromolecule #3: AMINO GROUP

MacromoleculeName: AMINO GROUP / type: ligand / ID: 3 / Number of copies: 15 / Formula: NH2
Molecular weightTheoretical: 16.023 Da
Chemical component information

ChemComp-NH2:
AMINO GROUP

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Macromolecule #4: 1,3-dimethylbenzene

MacromoleculeName: 1,3-dimethylbenzene / type: ligand / ID: 4 / Number of copies: 15 / Formula: 8VH
Molecular weightTheoretical: 106.165 Da
Chemical component information

ChemComp-8VH:
1,3-dimethylbenzene

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

Concentration4.5 mg/mL
BufferpH: 7.6
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 59.495 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.6 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 4.79 Å
Applied symmetry - Helical parameters - Δ&Phi: -2.85 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 69100
CTF correctionType: NONE
Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementProtocol: BACKBONE TRACE
Output model

PDB-9b3a:
filament of type 1 KD-mxyl miniature tau macrocycle derived from 4R tauopathic fold

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