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TitleTau filaments with the Alzheimer fold in human MAPT mutants V337M and R406W.
Journal, issue, pagesNat Struct Mol Biol, Year 2025
Publish dateMar 5, 2025
AuthorsChao Qi / Sofia Lövestam / Alexey G Murzin / Sew Peak-Chew / Catarina Franco / Marika Bogdani / Caitlin Latimer / Jill R Murrell / Patrick W Cullinane / Zane Jaunmuktane / Thomas D Bird / Bernardino Ghetti / Sjors H W Scheres / Michel Goedert /
PubMed AbstractFrontotemporal dementia (FTD) and Alzheimer's disease (AD) are the most common forms of early-onset dementia. Unlike AD, FTD begins with behavioral changes before the development of cognitive ...Frontotemporal dementia (FTD) and Alzheimer's disease (AD) are the most common forms of early-onset dementia. Unlike AD, FTD begins with behavioral changes before the development of cognitive impairment. Dominantly inherited mutations in MAPT, the microtubule-associated protein tau gene, give rise to cases of FTD and parkinsonism linked to chromosome 17. These individuals develop abundant filamentous tau inclusions in brain cells in the absence of β-amyloid deposits. Here, we used cryo-electron microscopy to determine the structures of tau filaments from the brains of human MAPT mutants V337M and R406W. Both amino acid substitutions gave rise to tau filaments with the Alzheimer fold, which consisted of paired helical filaments in all V337M and R406W cases and of straight filaments in two V337M cases. We also identified another assembly of the Alzheimer fold into triple tau filaments in a V337M case. Filaments assembled from recombinant tau (297-391) with substitution V337M had the Alzheimer fold and showed an increased rate of assembly.
External linksNat Struct Mol Biol / PubMed:40044789
MethodsEM (helical sym.)
Resolution2.3 - 3.3 Å
Structure data

19846

9eo7

EMDB-19846, PDB-9eo7:
PHF type tau filament from V337M mutant
Method: EM (helical sym.) / Resolution: 2.8 Å

19849

9eo9

EMDB-19849: PHF type tau filament from V337M mutant
PDB-9eo9: SF type tau filament from V337M mutant
Method: EM (helical sym.) / Resolution: 3.3 Å

19852

9eoe

EMDB-19852: PHF type tau filament from V337M mutant
PDB-9eoe: TF type tau filament from V337M mutant
Method: EM (helical sym.) / Resolution: 2.3 Å

19854

9eog

EMDB-19854, PDB-9eog:
PHF type tau filament from R406W mutant
Method: EM (helical sym.) / Resolution: 3.0 Å

19855

9eoh

EMDB-19855, PDB-9eoh:
PHF type tau filament from in vitro V337M mutant
Method: EM (helical sym.) / Resolution: 2.8 Å

Source
  • homo sapiens (human)
KeywordsPROTEIN FIBRIL / PHF / tau filament / V337M / TF / R406W

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