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Structure paper

TitleDisease-specific tau filaments assemble via polymorphic intermediates.
Journal, issue, pagesNature, Vol. 625, Issue 7993, Page 119-125, Year 2024
Publish dateNov 29, 2023
AuthorsSofia Lövestam / David Li / Jane L Wagstaff / Abhay Kotecha / Dari Kimanius / Stephen H McLaughlin / Alexey G Murzin / Stefan M V Freund / Michel Goedert / Sjors H W Scheres /
PubMed AbstractIntermediate species in the assembly of amyloid filaments are believed to play a central role in neurodegenerative diseases and may constitute important targets for therapeutic intervention. However, ...Intermediate species in the assembly of amyloid filaments are believed to play a central role in neurodegenerative diseases and may constitute important targets for therapeutic intervention. However, structural information about intermediate species has been scarce and the molecular mechanisms by which amyloids assemble remain largely unknown. Here we use time-resolved cryogenic electron microscopy to study the in vitro assembly of recombinant truncated tau (amino acid residues 297-391) into paired helical filaments of Alzheimer's disease or into filaments of chronic traumatic encephalopathy. We report the formation of a shared first intermediate amyloid filament, with an ordered core comprising residues 302-316. Nuclear magnetic resonance indicates that the same residues adopt rigid, β-strand-like conformations in monomeric tau. At later time points, the first intermediate amyloid disappears and we observe many different intermediate amyloid filaments, with structures that depend on the reaction conditions. At the end of both assembly reactions, most intermediate amyloids disappear and filaments with the same ordered cores as those from human brains remain. Our results provide structural insights into the processes of primary and secondary nucleation of amyloid assembly, with implications for the design of new therapies.
External linksNature / PubMed:38030728 / PubMed Central
MethodsEM (helical sym.)
Resolution1.75 - 21.1 Å
Structure data

EMDB-17806, PDB-8ppo:
First Intermediate Amyloid (FIA) - Tau
Method: EM (helical sym.) / Resolution: 2.0 Å

EMDB-18070, PDB-8q27:
Tau: AD-MIA1
Method: EM (helical sym.) / Resolution: 2.02 Å

EMDB-18109, PDB-8q2j:
Tau - AD-MIA2
Method: EM (helical sym.) / Resolution: 2.23 Å

EMDB-18111, PDB-8q2k:
Tau - AD-MIA3
Method: EM (helical sym.) / Resolution: 2.88 Å

EMDB-18112, PDB-8q2l:
Tau - AD-MIA4
Method: EM (helical sym.) / Resolution: 2.2 Å

EMDB-18215, PDB-8q7f:
Tau - AD-MIA5
Method: EM (helical sym.) / Resolution: 3.72 Å

EMDB-18219, PDB-8q7l:
Tau - AD-MIA6 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 2.82 Å

EMDB-18224, PDB-8q7m:
Tau - AD-MIA7 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 3.26 Å

EMDB-18228, PDB-8q7p:
Tau - AD-MIA8 (intermediate amyloid)
Method: EM (helical sym.) / Resolution: 3.28 Å

EMDB-18233, PDB-8q7t:
Tau - AD-MIA11
Method: EM (helical sym.) / Resolution: 3.0 Å

EMDB-18249, PDB-8q88:
Tau - AD-LIA2 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 2.95 Å

EMDB-18250, PDB-8q8c:
Tau - AD-MIA10 (intermediate amyloid)
Method: EM (helical sym.) / Resolution: 1.92 Å

EMDB-18251, PDB-8q8d:
Tau - AD-LIA6 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 3.04 Å

EMDB-18252, PDB-8q8e:
Tau - AD-LIA4 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 3.81 Å

EMDB-18253, PDB-8q8f:
Tau - AD-LIA5 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 2.93 Å

EMDB-18254, PDB-8q8l:
Tau - AD-LIA7 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 3.04 Å

EMDB-18255, PDB-8q8m:
Tau - AD-PHF long crossover
Method: EM (helical sym.) / Resolution: 2.95 Å

EMDB-18258, PDB-8q8r:
Tau - AD-PHF
Method: EM (helical sym.) / Resolution: 2.1 Å

EMDB-18259, PDB-8q8s:
Tau - AD-THF
Method: EM (helical sym.) / Resolution: 2.68 Å

EMDB-18261, PDB-8q8u:
Tau - CTE-MIA1 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 3.3 Å

EMDB-18262, PDB-8q8v:
Tau - CTE-MIA3
Method: EM (helical sym.) / Resolution: 3.8 Å

EMDB-18263, PDB-8q8w:
Tau - CTE-MIA4 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 2.85 Å

EMDB-18264, PDB-8q8x:
Tau - CTE-MIA5 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 2.54 Å

EMDB-18265, PDB-8q8y:
Tau - CTE-MIA6 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 2.88 Å

EMDB-18266, PDB-8q8z:
Tau - CTE-MIA7 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 3.16 Å

EMDB-18270, PDB-8q97:
Tau - CTE-MIA9 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 2.99 Å

EMDB-18271, PDB-8q98:
Tau - CTE-MIA8 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 1.75 Å

EMDB-18272, PDB-8q99:
Tau - CTE-MIA10 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 2.7 Å

EMDB-18273, PDB-8q9a:
Tau - CTE-MIA11 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 3.04 Å

EMDB-18275, PDB-8q9b:
Tau - CTE-MIA13 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 3.1 Å

EMDB-18276, PDB-8q9c:
Tau - CTE-MIA14 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 3.4 Å

EMDB-18277, PDB-8q9d:
Tau - CTE-MIA15 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 3.16 Å

EMDB-18278, PDB-8q9e:
Tau - CTE-MIA18 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 2.97 Å

EMDB-18279, PDB-8q9f:
Tau - CTE-LIA3 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 1.91 Å

EMDB-18280, PDB-8q9g:
Tau - CTE-LIA5 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 2.65 Å

EMDB-18281, PDB-8q9h:
Tau - CTE-LIA4 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 2.18 Å

EMDB-18282, PDB-8q9i:
Tau - CTE-LIA6 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 2.56 Å

EMDB-18283, PDB-8q9j:
Tau - CTE-LIA7 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 2.96 Å

EMDB-18284, PDB-8q9k:
Tau - CTE-LIA13 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 3.2 Å

EMDB-18285, PDB-8q9l:
Tau - CTE-LIA14 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 2.76 Å

EMDB-18286, PDB-8q9m:
Tau - CTE-type I (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 2.65 Å

EMDB-18287: Tau - CTE-type II (tau intermediate amyloid)
PDB-8q9o: CTE tau intermediate amyloid (LIA-17)
Method: EM (helical sym.) / Resolution: 3.1 Å

EMDB-18331, PDB-8qcp:
Tau - AD-LIA8 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 3.21 Å

EMDB-18333, PDB-8qcr:
Tau - CTE-MIA12 (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 2.75 Å

EMDB-18344: AD Tau intermediate amyloid (LIA-1)
Method: EM (helical sym.) / Resolution: 7.2 Å

EMDB-18347: AD Tau intermediate amyloid (LIA-3)
Method: EM (helical sym.) / Resolution: 9.0 Å

EMDB-18348: AD Tau intermediate amyloid (MIA-9)
Method: EM (helical sym.) / Resolution: 7.34 Å

EMDB-18349: AD Tau intermediate amyloid (QHF)
Method: EM (helical sym.) / Resolution: 4.28 Å

EMDB-18354: CTE Tau intermediate amyloid (MIA-2)
Method: EM (helical sym.) / Resolution: 4.22 Å

EMDB-18355: CTE Tau intermediate amyloid (MIA-16)
Method: EM (helical sym.) / Resolution: 4.59 Å

EMDB-18356: CTE Tau intermediate amyloid (MIA-19)
Method: EM (helical sym.) / Resolution: 6.73 Å

EMDB-18357: CTE Tau intermediate amyloid (MIA-20)
Method: EM (helical sym.) / Resolution: 5.02 Å

EMDB-18358: CTE Tau intermediate amyloid (LIA-1)
Method: EM (helical sym.) / Resolution: 8.56 Å

EMDB-18359: CTE Tau intermediate amyloid (LIA-2)
Method: EM (helical sym.) / Resolution: 5.97 Å

EMDB-18360: CTE Tau intermediate amyloid (LIA-8)
Method: EM (helical sym.) / Resolution: 8.55 Å

EMDB-18361: CTE Tau intermediate amyloid (LIA-9)
Method: EM (helical sym.) / Resolution: 5.97 Å

EMDB-18362: CTE Tau intermediate amyloid (LIA-10)
Method: EM (helical sym.) / Resolution: 21.1 Å

EMDB-18363: CTE Tau intermediate amyloid (LIA-11)
Method: EM (helical sym.) / Resolution: 8.11 Å

EMDB-18364: CTE Tau intermediate amyloid (LIA-12)
Method: EM (helical sym.) / Resolution: 3.86 Å

EMDB-18365: CTE Tau intermediate amyloid (LIA-15)
Method: EM (helical sym.) / Resolution: 5.27 Å

EMDB-18366: CTE Tau intermediate amyloid (LIA-16)
Method: EM (helical sym.) / Resolution: 4.33 Å

EMDB-18448, PDB-8qjj:
CTE type II (tau intermediate amyloid)
Method: EM (helical sym.) / Resolution: 3.35 Å

Source
  • homo sapiens (human)
KeywordsPROTEIN FIBRIL / Amyloid / tau

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