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TitleCryo-EM Structures of Chronic Traumatic Encephalopathy Tau Filaments with PET Ligand Flortaucipir.
Journal, issue, pagesJ Mol Biol, Vol. 435, Issue 11, Page 168025, Year 2023
Publish dateJun 1, 2023
AuthorsYang Shi / Bernardino Ghetti / Michel Goedert / Sjors H W Scheres /
PubMed AbstractPositron emission tomography (PET) imaging allows monitoring the progression of amyloid aggregation in the living brain. [F]-Flortaucipir is the only approved PET tracer compound for the ...Positron emission tomography (PET) imaging allows monitoring the progression of amyloid aggregation in the living brain. [F]-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.
External linksJ Mol Biol / PubMed:37330290 / PubMed Central
MethodsEM (helical sym.)
Resolution2.6 - 3.66 Å
Structure data

16329

8byn

EMDB-16329, PDB-8byn:
Chronic traumatic encephalopathy tau filaments with PET ligand flortaucipir
Method: EM (helical sym.) / Resolution: 2.6 Å

EMDB-35403: Paired helical filament from Alzheimer's disease brain with PET ligand flortaucipir (+flortaucipir)
Method: EM (helical sym.) / Resolution: 2.7 Å

EMDB-35404: Paired helical filament from Alzheimer's disease brain incubated with DMSO without PET ligand flortaucipir (-flortaucipir)
Method: EM (helical sym.) / Resolution: 2.68 Å

EMDB-35405: Paired helical filament from primary age-related tauopathy brain with PET ligand flortaucipir (+flortaucipir)
Method: EM (helical sym.) / Resolution: 3.43 Å

EMDB-35406: Straight filament from primary age-related tauopathy brain with PET ligand flortaucipir (+flortaucipir)
Method: EM (helical sym.) / Resolution: 2.62 Å

EMDB-35407: Paired helical filament from primary age-related tauopathy brain incubated with DMSO without PET ligand flortaucipir (-flortaucipir)
Method: EM (helical sym.) / Resolution: 3.66 Å

EMDB-35408: Straight filament from primary age-related tauopathy brain incubated with DMSO without PET ligand flortaucipir (-flortaucipir)
Method: EM (helical sym.) / Resolution: 2.7 Å

EMDB-35409: Chronic traumatic encephalopathy type I tau filaments from primary age-related tauopathy brain incubated with DMSO without PET ligand flortaucipir (-flortaucipir)
Method: EM (helical sym.) / Resolution: 2.69 Å

Chemicals

ChemComp-S9C:
7-(6-fluoranylpyridin-3-yl)-5~{H}-pyrido[4,3-b]indole

Source
  • homo sapiens (human)
KeywordsPROTEIN FIBRIL / Chronic traumatic encephalopathy / Primary age-related tauopathy / Tau filaments / PET ligand / Flortaucipir

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