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TitlePosttranslational Modifications Mediate the Structural Diversity of Tauopathy Strains.
Journal, issue, pagesCell, Vol. 180, Issue 4, Page 633-644.e12, Year 2020
Publish dateFeb 20, 2020
AuthorsTamta Arakhamia / Christina E Lee / Yari Carlomagno / Duc M Duong / Sean R Kundinger / Kevin Wang / Dewight Williams / Michael DeTure / Dennis W Dickson / Casey N Cook / Nicholas T Seyfried / Leonard Petrucelli / Anthony W P Fitzpatrick /
PubMed AbstractTau aggregation into insoluble filaments is the defining pathological hallmark of tauopathies. However, it is not known what controls the formation and templated seeding of strain-specific structures ...Tau aggregation into insoluble filaments is the defining pathological hallmark of tauopathies. However, it is not known what controls the formation and templated seeding of strain-specific structures associated with individual tauopathies. Here, we use cryo-electron microscopy (cryo-EM) to determine the structures of tau filaments from corticobasal degeneration (CBD) human brain tissue. Cryo-EM and mass spectrometry of tau filaments from CBD reveal that this conformer is heavily decorated with posttranslational modifications (PTMs), enabling us to map PTMs directly onto the structures. By comparing the structures and PTMs of tau filaments from CBD and Alzheimer's disease, it is found that ubiquitination of tau can mediate inter-protofilament interfaces. We propose a structure-based model in which cross-talk between PTMs influences tau filament structure, contributing to the structural diversity of tauopathy strains. Our approach establishes a framework for further elucidating the relationship between the structures of polymorphic fibrils, including their PTMs, and neurodegenerative disease.
External linksCell / PubMed:32032505 / PubMed Central
MethodsEM (helical sym.)
Resolution3.3 - 4.3 Å
Structure data

EMDB-21200, PDB-6vh7:
Doublet Tau Fibril from Corticobasal Degeneration Human Brain Tissue
Method: EM (helical sym.) / Resolution: 3.8 Å

EMDB-21201, PDB-6vha:
Singlet Tau Fibril from Corticobasal Degeneration Human Brain Tissue
Method: EM (helical sym.) / Resolution: 4.3 Å

EMDB-21207, PDB-6vhl:
Paired Helical Filament from Alzheimer's Disease Human Brain Tissue
Method: EM (helical sym.) / Resolution: 3.3 Å

PDB-6vi3:
Straight Filament from Alzheimer's Disease Human Brain Tissue
Method: ELECTRON MICROSCOPY / Resolution: 3.3 Å

Chemicals

ChemComp-GLY:
GLYCINE / Glycine

Source
  • homo sapiens (human)
KeywordsPROTEIN FIBRIL / Pathological amyloid fibril / cross-beta fold / parallel beta-sheets / Pathological amyloid fibril cross-beta fold parallel beta-sheets

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