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- PDB-8fnz: Acetylated tau repeat 1 and 2 fragment (AcR1R2) -

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Basic information

Entry
Database: PDB / ID: 8fnz
TitleAcetylated tau repeat 1 and 2 fragment (AcR1R2)
ComponentsMicrotubule-associated protein tau, acetylated repeat 1 and 2 fragment
KeywordsPROTEIN FIBRIL / Amyloid motif acetylation tau repeat domain post-translational modification
Function / homology
Function and homology information


plus-end-directed organelle transport along microtubule / axonal transport / histone-dependent DNA binding / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / positive regulation of protein localization to synapse / microtubule lateral binding / tubulin complex ...plus-end-directed organelle transport along microtubule / axonal transport / histone-dependent DNA binding / neurofibrillary tangle assembly / positive regulation of diacylglycerol kinase activity / negative regulation of establishment of protein localization to mitochondrion / neurofibrillary tangle / positive regulation of protein localization to synapse / microtubule lateral binding / tubulin complex / phosphatidylinositol bisphosphate binding / main axon / regulation of long-term synaptic depression / negative regulation of kinase activity / negative regulation of tubulin deacetylation / generation of neurons / regulation of chromosome organization / positive regulation of protein localization / rRNA metabolic process / internal protein amino acid acetylation / regulation of mitochondrial fission / intracellular distribution of mitochondria / axonal transport of mitochondrion / axon development / central nervous system neuron development / regulation of microtubule polymerization / microtubule polymerization / minor groove of adenine-thymine-rich DNA binding / lipoprotein particle binding / dynactin binding / apolipoprotein binding / glial cell projection / negative regulation of mitochondrial membrane potential / protein polymerization / negative regulation of mitochondrial fission / axolemma / Caspase-mediated cleavage of cytoskeletal proteins / regulation of microtubule polymerization or depolymerization / positive regulation of axon extension / regulation of microtubule cytoskeleton organization / Activation of AMPK downstream of NMDARs / supramolecular fiber organization / regulation of cellular response to heat / stress granule assembly / cytoplasmic microtubule organization / regulation of calcium-mediated signaling / axon cytoplasm / positive regulation of microtubule polymerization / somatodendritic compartment / cellular response to brain-derived neurotrophic factor stimulus / synapse assembly / phosphatidylinositol binding / nuclear periphery / cellular response to nerve growth factor stimulus / positive regulation of superoxide anion generation / protein phosphatase 2A binding / regulation of autophagy / astrocyte activation / response to lead ion / synapse organization / microglial cell activation / Hsp90 protein binding / regulation of synaptic plasticity / PKR-mediated signaling / protein homooligomerization / memory / cytoplasmic ribonucleoprotein granule / microtubule cytoskeleton organization / cellular response to reactive oxygen species / SH3 domain binding / activation of cysteine-type endopeptidase activity involved in apoptotic process / microtubule cytoskeleton / neuron projection development / cell-cell signaling / protein-macromolecule adaptor activity / actin binding / single-stranded DNA binding / cellular response to heat / protein-folding chaperone binding / cell body / growth cone / microtubule binding / double-stranded DNA binding / microtubule / amyloid fibril formation / sequence-specific DNA binding / dendritic spine / learning or memory / nuclear speck / 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
Similarity search - Function
: / Microtubule associated protein, tubulin-binding repeat / Microtubule-associated protein Tau / 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: 3.88 Å
AuthorsLi, L. / Nguyen, A.B. / Mullapudi, V. / Joachimiak, L.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)1U01CA242115 United States
Welch FoundationI-1928-20200401 United States
Chan Zuckerberg Initiative2018-191983 United States
CitationJournal: Structure / Year: 2023
Title: Disease-associated patterns of acetylation stabilize tau fibril formation.
Authors: Li Li / Binh A Nguyen / Vishruth Mullapudi / Yang Li / Lorena Saelices / Lukasz A Joachimiak /
Abstract: Assembly of tau into beta-sheet-rich amyloids dictates the pathology of a diversity of diseases. Lysine acetylation has been proposed to drive tau amyloid assembly, but no direct mechanism has ...Assembly of tau into beta-sheet-rich amyloids dictates the pathology of a diversity of diseases. Lysine acetylation has been proposed to drive tau amyloid assembly, but no direct mechanism has emerged. Using tau fragments, we identify patterns of acetylation that flank amyloidogenic motifs on the tau fragments that promote rapid fibril assembly. We determined a 3.9 Å cryo-EM amyloid fibril structure assembled from an acetylated tau fragment uncovering how lysine acetylation can mediate gain-of-function interactions. Comparison of the structure to an ex vivo tauopathy fibril reveals regions of structural similarity. Finally, we show that fibrils encoding disease-associated patterns of acetylation are active in cell-based tau aggregation assays. Our data uncover the dual role of lysine residues in limiting tau aggregation while their acetylation leads to stabilizing pro-aggregation interactions. Design of tau sequence with specific acetylation patterns may lead to controllable tau aggregation to direct folding of tau into distinct amyloid folds.
History
DepositionDec 29, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 28, 2023Provider: repository / Type: Initial release
Revision 1.1Jul 5, 2023Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Sep 20, 2023Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
G: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
F: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
H: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
E: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
A: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
I: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
J: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
K: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
L: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
C: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
B: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
D: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
R: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
S: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
Q: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
T: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
X: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
P: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
O: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
N: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
M: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
V: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
W: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
U: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
r: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
s: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
q: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
t: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
x: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
p: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
o: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
n: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
m: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
v: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
w: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
u: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
g: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
f: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
h: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
e: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
a: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
i: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
j: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
k: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
l: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
c: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
b: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment
d: Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment


Theoretical massNumber of molelcules
Total (without water)99,52148
Polymers99,52148
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: scanning transmission electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein/peptide ...
Microtubule-associated protein tau, acetylated repeat 1 and 2 fragment


Mass: 2073.352 Da / Num. of mol.: 48 / Fragment: acetylated repeat 1 and 2 fragment (AcR1R2) / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P10636
Has ligand of interestN

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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: Acetylated tau repeat 1 and 2 fragment (AcR1R2) / Type: COMPLEX / Details: Chemically synthesized / Entity ID: all / Source: SYNTHETIC
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4 / Details: This is PBS (1x)
Buffer component
IDConc.NameFormulaBuffer-ID
1137 mMSodium ChlorideNaCl1
22.7 mMPotassium ChlorideKCl1
38 mMDisodium hydrogen phosphateNa2HPO41
42 mMPotassium dihydrogen phosphateKH2PO41
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: we used 0.5 mM of the peptide to make the fibril
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 295 K
Details: We used blot-force of -5, and blot-time of 4 seconds.

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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 magnification: 105000 X / Nominal defocus max: 2400 nm / Nominal defocus min: 1200 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 4.5 sec. / Electron dose: 52 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 5901

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
EM software
IDNameVersionCategory
1crYOLO1.8particle selection
2SerialEM3.8image acquisition
4RELION3.1CTF correction
7Coot0.9.8.1model fitting
9PHENIX1.20.1model refinement
10RELION3.1initial Euler assignment
11RELION3.1final Euler assignment
12RELION3.1classification
13RELION3.13D reconstruction
CTF correctionType: NONE
Helical symmertyAngular rotation/subunit: -1 ° / Axial rise/subunit: 4.75 Å / Axial symmetry: C1
3D reconstructionResolution: 3.88 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 45674 / Num. of class averages: 1 / Symmetry type: HELICAL
Atomic model buildingProtocol: OTHER / Target criteria: Cross-correlation coefficient
RefinementHighest resolution: 3.88 Å

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