8BG9

Murine amyloid-beta filaments with the Arctic mutation (E22G) from APP(NL-G-F) mouse brains | ABeta

Summary for 8BG9

• Entry DOI: 10.2210/pdb8bg9/pdb
• EMDB information: 16027
• Descriptor: Amyloid-beta protein 40 (1 entity in total)
• Functional Keywords: amyloid, amyloid-beta, arctic mutation, app, nl-g-f, mouse brains, filaments, e22g, e693g, protein fibril
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 2
• Total formula weight: 8161.08

Authors

Yang, Y.,Zhang, W.J.,Murzin, A.G.,Schweighauser, M.,Huang, M.,Lovestam, S.K.A.,Peak-Chew, S.Y.,Macdonald, J.,Lavenir, I.,Ghetti, B.,Graff, C.,Kumar, A.,Nordber, A.,Goedert, M.,Scheres, S.H.W. (deposition date: 2022-10-27, release date: 2023-01-18, Last modification date: 2024-07-24)

Primary citation

Yang, Y.,Zhang, W.,Murzin, A.G.,Schweighauser, M.,Huang, M.,Lovestam, S.,Peak-Chew, S.Y.,Saito, T.,Saido, T.C.,Macdonald, J.,Lavenir, I.,Ghetti, B.,Graff, C.,Kumar, A.,Nordberg, A.,Goedert, M.,Scheres, S.H.W.
Cryo-EM structures of amyloid-beta filaments with the Arctic mutation (E22G) from human and mouse brains.
Acta Neuropathol, 145:325-333, 2023

PubMed Abstract: The Arctic mutation, encoding E693G in the amyloid precursor protein (APP) gene [E22G in amyloid-β (Aβ)], causes dominantly inherited Alzheimer's disease. Here, we report the high-resolution cryo-EM structures of Aβ filaments from the frontal cortex of a previously described case (AβPParc1) with the Arctic mutation. Most filaments consist of two pairs of non-identical protofilaments that comprise residues V12-V40 (human Arctic fold A) and E11-G37 (human Arctic fold B). They have a substructure (residues F20-G37) in common with the folds of type I and type II Aβ42. When compared to the structures of wild-type Aβ42 filaments, there are subtle conformational changes in the human Arctic folds, because of the lack of a side chain at G22, which may strengthen hydrogen bonding between mutant Aβ molecules and promote filament formation. A minority of Aβ42 filaments of type II was also present, as were tau paired helical filaments. In addition, we report the cryo-EM structures of Aβ filaments with the Arctic mutation from mouse knock-in line App. Most filaments are made of two identical mutant protofilaments that extend from D1 to G37 (App murine Arctic fold). In a minority of filaments, two dimeric folds pack against each other in an anti-parallel fashion. The App murine Arctic fold differs from the human Arctic folds, but shares some substructure.

PubMed: 36611124
DOI: 10.1007/s00401-022-02533-1

Experimental method

ELECTRON MICROSCOPY (3.5 Å)