9JB1

Cryo-EM structure of the type I amyloid-beta 42 fibril containing a D-Asp at positions 7 and 23

This is a non-PDB format compatible entry.

Summary for 9JB1

• Entry DOI: 10.2210/pdb9jb1/pdb
• EMDB information: 61304
• Descriptor: Amyloid-beta precursor protein (1 entity in total)
• Functional Keywords: aggregation, protein fibril
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 12
• Total formula weight: 54241.04

Authors

Hsiao, L.C.,Lee, C.H.,Hsu, M.F.,Hsu, S.T. (deposition date: 2024-08-26, release date: 2025-03-26, Last modification date: 2025-04-09)

Primary citation

Hsiao, L.C.,Lee, C.H.,Mazmanian, K.,Yoshida, M.,Ito, G.,Murata, T.,Utsunomiya-Tate, N.,Haino, T.,Tate, S.I.,Hsu, S.D.
Impacts of D-aspartate on the Aggregation Kinetics and Structural Polymorphism of Amyloid beta Peptide 1-42.
J.Mol.Biol., 437:169092-169092, 2025

PubMed Abstract: Isomerization of L-Aspartate (L-Asp) into D-aspartate (D-Asp) occurs naturally in proteins at a rate that is much faster than that of other amino acid types. Accumulation of D-Asp is age-dependent, which could alter protein structures and, therefore, functions. Site-specific introduction of D-Asp can accelerate aggregation kinetics of a variety of proteins associated with misfolding diseases. Here, we showed by thioflavin T fluorescence that the isomerization of L-Asp at different positions of amyloid β peptide 1-42 (Aβ42) generates opposing effects on its aggregation kinetics. We further determined the atomic structures of Aβ42 amyloid fibrils harboring a single D-Asp at position 23 and two D-Asp at positions 7 and 23 by cryo-electron microscopy helical reconstruction - cross-validated by cryo-electron tomography and atomic force microscopy - to reveal how D-Asp contributes to the formation of a unique triple stranded amyloid fibril structure stabilized by two threads of well-ordered water molecules. These findings provide crucial insights into how the conversion from L- to D-Asp influences the aggregation propensity and amyloid polymorphism of Aβ42.

PubMed: 40090459
DOI: 10.1016/j.jmb.2025.169092

Experimental method

ELECTRON MICROSCOPY (2.5 Å)