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- PDB-9fh6: Cryo-EM Structure of Tau Filaments from Individuals Carrying the ... -

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Basic information

Entry
Database: PDB / ID: 9fh6
TitleCryo-EM Structure of Tau Filaments from Individuals Carrying the Uppsala AbetaUpp(1-42)delta(19-24) Mutation
ComponentsMicrotubule-associated protein tau
KeywordsPROTEIN FIBRIL / Amyloid 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 / axon development / axonal transport of mitochondrion / rRNA metabolic process / regulation of mitochondrial fission / regulation of microtubule-based movement / central nervous system neuron development / intracellular distribution of mitochondria / regulation of chromosome organization / 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 / protein polymerization / main axon / Caspase-mediated cleavage of cytoskeletal proteins / regulation of microtubule polymerization or depolymerization / glial cell projection / negative regulation of mitochondrial fission / axolemma / positive regulation of axon extension / neurofibrillary tangle assembly / regulation of cellular response to heat / positive regulation of microtubule polymerization / positive regulation of protein localization / Activation of AMPK downstream of NMDARs / positive regulation of superoxide anion generation / cytoplasmic microtubule organization / cellular response to brain-derived neurotrophic factor stimulus / regulation of long-term synaptic depression / supramolecular fiber organization / regulation of calcium-mediated signaling / axon cytoplasm / somatodendritic compartment / synapse assembly / astrocyte activation / nuclear periphery / phosphatidylinositol binding / protein phosphatase 2A binding / enzyme inhibitor activity / stress granule assembly / regulation of autophagy / regulation of microtubule cytoskeleton organization / cellular response to reactive oxygen species / microglial cell activation / cellular response to nerve growth factor stimulus / Hsp90 protein binding / regulation of synaptic plasticity / memory / SH3 domain binding / synapse organization / protein homooligomerization / PKR-mediated signaling / microtubule cytoskeleton organization / response to lead ion / neuron projection development / cytoplasmic ribonucleoprotein granule / microtubule cytoskeleton / cell-cell signaling / cellular response to heat / single-stranded DNA binding / growth cone / protein-folding chaperone binding / actin binding / cell body / double-stranded DNA binding / sequence-specific DNA binding / microtubule binding / amyloid fibril formation / dendritic spine / microtubule / learning or memory / protein-macromolecule adaptor activity / 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)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsZielinski, M. / Peralta Reyes, F.S. / Gremer, L. / Pagnon de la Vega, M. / Roeder, C. / Heidler, T.V. / Syvaenen, S. / Willbold, D. / Sehlin, D. / Ingelsson, M. / Schroeder, G.F.
Funding support Germany, 1items
OrganizationGrant numberCountry
Helmholtz AssociationIVF Germany
CitationJournal: Acta Neuropathol Commun / Year: 2025
Title: Cryo-EM studies of amyloid-β fibrils from human and murine brains carrying the Uppsala APP mutation (Δ690-695).
Authors: Mara Zielinski / Fernanda S Peralta Reyes / Lothar Gremer / Simon Sommerhage / María Pagnon de la Vega / Christine Röder / Thomas V Heidler / Stina Syvänen / Dieter Willbold / Dag Sehlin ...Authors: Mara Zielinski / Fernanda S Peralta Reyes / Lothar Gremer / Simon Sommerhage / María Pagnon de la Vega / Christine Röder / Thomas V Heidler / Stina Syvänen / Dieter Willbold / Dag Sehlin / Martin Ingelsson / Gunnar F Schröder /
Abstract: Today, 13 intra-amyloid-β (Aβ) amyloid precursor protein (APP) gene mutations are known to cause familial Alzheimer's disease (AD). Most of them are point mutations causing an increased production ...Today, 13 intra-amyloid-β (Aβ) amyloid precursor protein (APP) gene mutations are known to cause familial Alzheimer's disease (AD). Most of them are point mutations causing an increased production or a change in the conformation of Aβ. The Uppsala APP mutation (Δ690-695 in APP, Δ19-24 in Aβ) is the first known multi-codon deletion causing autosomal dominant AD. Here, we applied cryo-electron microscopy (cryo-EM) to investigate the structure of Aβ fibrils with the Uppsala APP mutation from tg-UppSwe mouse brain tissue. Murine AβUpp(1-42) are made of two identical S-shaped protofilaments with an ordered fibril core of S8-A42. The murine Aβ fold is almost identical to previously described human type II filaments, although the amino acid sequences differ considerably. In addition, we report the cryo-EM structure of Aβ fibrils from the temporal cortex of a patient with the Uppsala APP mutation. The observed structure of the human Aβ fold closely resembles previously described type I fibrils. Structural modeling suggests that these fibrils are composed of wild-type Aβ, which implies that AβUpp may be less soluble and thus not readily accessible for cryo-EM image processing and structure determination. Additionally, from the human sample we determined the structures of tau paired helical filaments and tau straight filaments, which are identical to those found in sporadic AD cases. Finally, we present the 3D cryo-EM structures of four dominant AβUpp(1-42) fibril polymorphs, formed in vitro. All four polymorphs differ from the observed folds of Uppsala Aβ in murine and human brain tissue, respectively.
History
DepositionMay 26, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 11, 2025Provider: repository / Type: Initial release
Revision 1.0Jun 11, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jun 11, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jun 11, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Jun 11, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 11, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Oct 22, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Microtubule-associated protein tau
B: Microtubule-associated protein tau
C: Microtubule-associated protein tau
D: Microtubule-associated protein tau
E: Microtubule-associated protein tau
F: Microtubule-associated protein tau
G: Microtubule-associated protein tau
H: Microtubule-associated protein tau
I: Microtubule-associated protein tau
J: Microtubule-associated protein tau


Theoretical massNumber of molelcules
Total (without water)79,40110
Polymers79,40110
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area50360 Å2
ΔGint-191 kcal/mol
Surface area29800 Å2
MethodPISA

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Components

#1: Protein
Microtubule-associated protein tau / Neurofibrillary tangle protein / Paired helical filament-tau / PHF-tau


Mass: 7940.141 Da / Num. of mol.: 10 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P10636
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: tau filaments / Type: TISSUE / Entity ID: all / Source: NATURAL
Source (natural)Organism: unidentified (others)
Buffer solutionpH: 7
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: 3000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameVersionCategory
9PHENIX1.20.1model refinement
10ISOLDE1.7.1model refinement
14RELION33D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 179.4 ° / Axial rise/subunit: 2.39 Å / Axial symmetry: C1
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 112719 / Symmetry type: HELICAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0045660
ELECTRON MICROSCOPYf_angle_d0.7267580
ELECTRON MICROSCOPYf_dihedral_angle_d6.303740
ELECTRON MICROSCOPYf_chiral_restr0.05860
ELECTRON MICROSCOPYf_plane_restr0.006960

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