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- PDB-9b3a: filament of type 1 KD-mxyl miniature tau macrocycle derived from ... -

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Basic information

Entry
Database: PDB / ID: 9b3a
Titlefilament of type 1 KD-mxyl miniature tau macrocycle derived from 4R tauopathic fold
Components
  • Microtubule-associated protein tau
  • SER-VAL-GLN-ILE-VAL-TYR-LYS
KeywordsPROTEIN FIBRIL / tauopathies / neurodegenerative disorders / seed-competent miniature tau macrocycle
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 / synapse organization / protein homooligomerization / PKR-mediated signaling / regulation of synaptic plasticity / SH3 domain binding / response to lead ion / 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 / actin binding / growth cone / 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 / 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 / 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
1,3-dimethylbenzene / AMINO GROUP / Microtubule-associated protein tau
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsXu, X. / Angera, J.I. / Rajewski, H.B. / Jiang, W. / Del Valle, R.J.
Funding support United States, 2items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 26, 2025Provider: repository / Type: Initial release
Revision 1.0Mar 26, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Mar 26, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Mar 26, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 26, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 26, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Mar 26, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Oct 8, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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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: SER-VAL-GLN-ILE-VAL-TYR-LYS
C: Microtubule-associated protein tau
D: SER-VAL-GLN-ILE-VAL-TYR-LYS
E: Microtubule-associated protein tau
F: SER-VAL-GLN-ILE-VAL-TYR-LYS
G: Microtubule-associated protein tau
H: SER-VAL-GLN-ILE-VAL-TYR-LYS
I: Microtubule-associated protein tau
J: SER-VAL-GLN-ILE-VAL-TYR-LYS
K: Microtubule-associated protein tau
L: SER-VAL-GLN-ILE-VAL-TYR-LYS
M: Microtubule-associated protein tau
N: SER-VAL-GLN-ILE-VAL-TYR-LYS
O: Microtubule-associated protein tau
P: SER-VAL-GLN-ILE-VAL-TYR-LYS
Q: Microtubule-associated protein tau
R: SER-VAL-GLN-ILE-VAL-TYR-LYS
S: Microtubule-associated protein tau
T: SER-VAL-GLN-ILE-VAL-TYR-LYS
U: Microtubule-associated protein tau
V: SER-VAL-GLN-ILE-VAL-TYR-LYS
W: Microtubule-associated protein tau
X: SER-VAL-GLN-ILE-VAL-TYR-LYS
Y: Microtubule-associated protein tau
Z: SER-VAL-GLN-ILE-VAL-TYR-LYS
a: Microtubule-associated protein tau
b: SER-VAL-GLN-ILE-VAL-TYR-LYS
c: Microtubule-associated protein tau
d: SER-VAL-GLN-ILE-VAL-TYR-LYS
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,02760
Polymers46,19530
Non-polymers1,83330
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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


Mass: 2242.640 Da / Num. of mol.: 15 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P10636
#2: Protein/peptide
SER-VAL-GLN-ILE-VAL-TYR-LYS


Mass: 836.995 Da / Num. of mol.: 15 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
#3: Chemical
ChemComp-NH2 / AMINO GROUP


Mass: 16.023 Da / Num. of mol.: 15 / Source method: obtained synthetically / Formula: NH2
#4: Chemical
ChemComp-8VH / 1,3-dimethylbenzene


Mass: 106.165 Da / Num. of mol.: 15 / Source method: obtained synthetically / Formula: C8H10
Has ligand of interestN
Has protein modificationY

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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: type 1 KD-mxyl miniature tau macrocycle derived from 4R tauopathic fold
Type: CELL / Entity ID: #1-#2 / Source: NATURAL
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.6
SpecimenConc.: 4.5 mg/ml / Embedding 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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 600 nm / C2 aperture diameter: 50 µm
Image recordingElectron dose: 59.495 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: NONE
Helical symmertyAngular rotation/subunit: -2.85 ° / Axial rise/subunit: 4.79 Å / Axial symmetry: C1
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 69100 / Symmetry type: HELICAL
Atomic model buildingProtocol: BACKBONE TRACE

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