2MXU

42-Residue Beta Amyloid Fibril

Summary for 2MXU

• Entry DOI: 10.2210/pdb2mxu/pdb
• NMR Information: BMRB: 25429
• Descriptor: Amyloid beta A4 protein (1 entity in total)
• Functional Keywords: amyloid fibril, amyloid beta, protein fibril
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P05067
• Total number of polymer chains: 12
• Total formula weight: 54241.04

Authors

Xiao, Y.,Ma, B.,McElheny, D.,Parthasarathy, S.,Long, F.,Hoshi, M.,Nussinov, R.,Ishii, Y. (deposition date: 2015-01-14, release date: 2015-05-06, Last modification date: 2024-05-01)

Primary citation

Xiao, Y.,Ma, B.,McElheny, D.,Parthasarathy, S.,Long, F.,Hoshi, M.,Nussinov, R.,Ishii, Y.
A beta (1-42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer's disease.
Nat.Struct.Mol.Biol., 22:499-505, 2015

PubMed Abstract: Increasing evidence has suggested that formation and propagation of misfolded aggregates of 42-residue human amyloid β (Aβ(1-42)), rather than of the more abundant Aβ(1-40), provokes the Alzheimer's disease cascade. However, structural details of misfolded Aβ(1-42) have remained elusive. Here we present the atomic model of an Aβ(1-42) amyloid fibril, from solid-state NMR (ssNMR) data. It displays triple parallel-β-sheet segments that differ from reported structures of Aβ(1-40) fibrils. Remarkably, Aβ(1-40) is incompatible with the triple-β-motif, because seeding with Aβ(1-42) fibrils does not promote conversion of monomeric Aβ(1-40) into fibrils via cross-replication. ssNMR experiments suggest that C-terminal Ala42, absent in Aβ(1-40), forms a salt bridge with Lys28 to create a self-recognition molecular switch that excludes Aβ(1-40). The results provide insight into the Aβ(1-42)-selective self-replicating amyloid-propagation machinery in early-stage Alzheimer's disease.

PubMed: 25938662
DOI: 10.1038/nsmb.2991

Experimental method

SOLID-STATE NMR