Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Cryo-EM reconstruction of heparin-induced 2N4R tau filaments

ABSTRACT:

SUBMITTER: Sjors H.W. Scheres

PROVIDER: EMPIAR-10243 | biostudies-other |

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Publications

Heparin-induced tau filaments are polymorphic and differ from those in Alzheimer's and Pick's diseases.

Zhang Wenjuan W Falcon Benjamin B Murzin Alexey G AG Fan Juan J Crowther R Anthony RA Goedert Michel M Scheres Sjors Hw SH

eLife 20190205

Assembly of microtubule-associated protein tau into filamentous inclusions underlies a range of neurodegenerative diseases. Tau filaments adopt different conformations in Alzheimer's and Pick's diseases. Here, we used cryo- and immuno- electron microscopy to characterise filaments that were assembled from recombinant full-length human tau with four (2N4R) or three (2N3R) microtubule-binding repeats in the presence of heparin. 2N4R tau assembles into multiple types of filaments, and the structure ...[more]

PMID: 30720432

Similar Datasets

Cryo-EM reconstruction of heparin-induced 2N3R tau filaments

Project description: Not available

| EMPIAR-10242 | biostudies-other

Cryo-EM structures of tau filaments from Alzheimer's disease.

Project description:Alzheimer's disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. The disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in the cerebral cortex. Neurofibrillary lesions comprise paired helical and straight tau filaments, whereas tau filaments with different morphologies characterize other neurodegenerative diseases. No high-resolution structures of tau filaments are available. Here we present cryo-electron microscopy (cryo-EM) maps at 3.4-3.5?Å resolution and corresponding atomic models of paired helical and straight filaments from the brain of an individual with Alzheimer's disease. Filament cores are made of two identical protofilaments comprising residues 306-378 of tau protein, which adopt a combined cross-?/?-helix structure and define the seed for tau aggregation. Paired helical and straight filaments differ in their inter-protofilament packing, showing that they are ultrastructural polymorphs. These findings demonstrate that cryo-EM allows atomic characterization of amyloid filaments from patient-derived material, and pave the way for investigation of a range of neurodegenerative diseases.

| S-EPMC5552202 | biostudies-literature

Cryo-EM structure of Alzheimer's disease tau filaments with PET ligand MK-6240.

Project description:Positron Emission Tomography (PET) ligands have advanced Alzheimer's disease (AD) diagnosis and treatment. Using autoradiography and cryo-EM, we identified AD brain tissue with elevated tau burden, purified filaments, and determined the structure of second-generation high avidity PET ligand MK-6240 at 2.31 Å resolution, which bound at a 1:1 ratio within the cleft of tau paired-helical filament (PHF), engaging with glutamine 351, lysine K353, and isoleucine 360. This information elucidates the basis of MK-6240 PET in quantifying PHF deposits in AD and may facilitate the structure-based design of superior ligands against tau amyloids.

| S-EPMC10542181 | biostudies-literature

Cryo-EM Structures of Chronic Traumatic Encephalopathy Tau Filaments with PET Ligand Flortaucipir.

Project description:Positron emission tomography (PET) imaging allows monitoring the progression of amyloid aggregation in the living brain. [18F]-Flortaucipir is the only approved PET tracer compound for the visualisation of tau aggregation. Here, we describe cryo-EM experiments on tau filaments in the presence and absence of flortaucipir. We used tau filaments isolated from the brain of an individual with Alzheimer's disease (AD), and from the brain of an individual with primary age-related tauopathy (PART) with a co-pathology of chronic traumatic encephalopathy (CTE). Unexpectedly, we were unable to visualise additional cryo-EM density for flortaucipir for AD paired helical or straight filaments (PHFs or SFs), but we did observe density for flortaucipir binding to CTE Type I filaments from the case with PART. In the latter, flortaucipir binds in a 1:1 molecular stoichiometry with tau, adjacent to lysine 353 and aspartate 358. By adopting a tilted geometry with respect to the helical axis, the 4.7 Å distance between neighbouring tau monomers is reconciled with the 3.5 Å distance consistent with π-π-stacking between neighbouring molecules of flortaucipir.

| S-EPMC7615338 | biostudies-literature

Cryo-EM structures of tau filaments from the brains of mice transgenic for human mutant P301S Tau.

Project description:Mice transgenic for human mutant P301S tau are widely used as models for human tauopathies. They develop neurodegeneration and abundant filamentous inclusions made of human mutant four-repeat tau. Here we used electron cryo-microscopy (cryo-EM) to determine the structures of tau filaments from the brains of Tg2541 and PS19 mice. Both lines express human P301S tau (0N4R for Tg2541 and 1N4R for PS19) on mixed genetic backgrounds and downstream of different promoters (murine Thy1 for Tg2541 and murine Prnp for PS19). The structures of tau filaments from Tg2541 and PS19 mice differ from each other and those of wild-type tau filaments from human brains. The structures of tau filaments from the brains of humans with mutations P301L, P301S or P301T in MAPT are not known. Filaments from the brains of Tg2541 and PS19 mice share a substructure at the junction of repeats 2 and 3, which comprises residues I297-V312 of tau and includes the P301S mutation. The filament core from the brainstem of Tg2541 mice consists of residues K274-H329 of tau and two disconnected protein densities. Two non-proteinaceous densities are also in evidence. The filament core from the cerebral cortex of line PS19 extends from residues G271-P364 of tau. One strong non-proteinaceous density is also present. Unlike the tau filaments from human brains, the sequences following repeat 4 are missing from the cores of tau filaments from the brains of Tg2541 and PS19 mice.

| S-EPMC10552433 | biostudies-literature

Cryo-EM structures of tau filaments from Alzheimer's disease with PET ligand APN-1607.

Project description:Tau and Aβ assemblies of Alzheimer's disease (AD) can be visualized in living subjects using positron emission tomography (PET). Tau assemblies comprise paired helical and straight filaments (PHFs and SFs). APN-1607 (PM-PBB3) is a recently described PET ligand for AD and other tau proteinopathies. Since it is not known where in the tau folds PET ligands bind, we used electron cryo-microscopy (cryo-EM) to determine the binding sites of APN-1607 in the Alzheimer fold. We identified two major sites in the β-helix of PHFs and SFs and a third major site in the C-shaped cavity of SFs. In addition, we report that tau filaments from posterior cortical atrophy (PCA) and primary age-related tauopathy (PART) are identical to those from AD. In support, fluorescence labelling showed binding of APN-1607 to intraneuronal inclusions in AD, PART and PCA. Knowledge of the binding modes of APN-1607 to tau filaments may lead to the development of new ligands with increased specificity and binding activity. We show that cryo-EM can be used to identify the binding sites of small molecules in amyloid filaments.

| S-EPMC8043864 | biostudies-literature

Cryo-EM reconstruction of tau filaments extracted from the brains of three individuals with Corticobasal degeneration

Project description: Not available

| EMPIAR-10340 | biostudies-other

Cryo-EM reconstructions of tau filaments in chronic traumatic encephalopathy

Project description: Not available

| EMPIAR-10313 | biostudies-other

Reconstruction of Average Subtracted Tubular Regions (RASTR) enables structure determination of tubular filaments by cryo-EM.

Project description:As the field of electron microscopy advances, the increasing complexity of samples being produced demand more involved processing methods. In this study, we have developed a new processing method for generating 3D reconstructions of tubular structures. Tubular biomolecules are common throughout many cellular processes and are appealing targets for biophysical research. Processing of tubules with helical symmetry is relatively straightforward for electron microscopy if the helical parameters are known, but tubular structures that deviate from helical symmetry (asymmetrical components, local but no global order, etc) present myriad issues. Here we present a new processing technique called Reconstruction of Average Subtracted Tubular Regions (RASTR), which was developed to reconstruct tubular structures without applying symmetry. We explain the RASTR approach and quantify its performance using three examples: a simulated symmetrical tubular filament, a symmetrical tubular filament from cryo-EM data, and a membrane tubule coated with locally ordered but not globally ordered proteins.

| S-EPMC7337063 | biostudies-literature

Cryo-EM micrographs of AD tau filaments with PET ligand Flortaucipir

Project description: Not available

| EMPIAR-11750 | biostudies-other