6oiz Citations

Structure of amyloid-β (20-34) with Alzheimer's-associated isomerization at Asp23 reveals a distinct protofilament interface.

Abstract

Amyloid-β (Aβ) harbors numerous posttranslational modifications (PTMs) that may affect Alzheimer's disease (AD) pathogenesis. Here we present the 1.1 Å resolution MicroED structure of an Aβ 20-34 fibril with and without the disease-associated PTM, L-isoaspartate, at position 23 (L-isoAsp23). Both wild-type and L-isoAsp23 protofilaments adopt β-helix-like folds with tightly packed cores, resembling the cores of full-length fibrillar Aβ structures, and both self-associate through two distinct interfaces. One of these is a unique Aβ interface strengthened by the isoaspartyl modification. Powder diffraction patterns suggest a similar structure may be adopted by protofilaments of an analogous segment containing the heritable Iowa mutation, Asp23Asn. Consistent with its early onset phenotype in patients, Asp23Asn accelerates aggregation of Aβ 20-34, as does the L-isoAsp23 modification. These structures suggest that the enhanced amyloidogenicity of the modified Aβ segments may also reduce the concentration required to achieve nucleation and therefore help spur the pathogenesis of AD.

Reviews - 6oiz mentioned but not cited (1)

  1. Electron Diffraction of 3D Molecular Crystals. Saha A, Nia SS, Rodríguez JA. Chem Rev 122 13883-13914 (2022)

Articles - 6oiz mentioned but not cited (1)



Reviews citing this publication (6)

  1. Molecular Damage in Aging. Gladyshev VN, Kritchevsky SB, Clarke SG, Cuervo AM, Fiehn O, de Magalhães JP, Mau T, Maes M, Moritz R, Niedernhofer LJ, Van Schaftingen E, Tranah GJ, Walsh K, Yura Y, Zhang B, Cummings SR. Nat Aging 1 1096-1106 (2021)
  2. Advances in methods for atomic resolution macromolecular structure determination. Thompson MC, Yeates TO, Rodriguez JA. F1000Res 9 F1000 Faculty Rev-667 (2020)
  3. Mass spectrometry analysis of tau and amyloid-beta in iPSC-derived models of Alzheimer's disease and dementia. Arber C, Alatza A, Leckey CA, Paterson RW, Zetterberg H, Wray S. J Neurochem 159 305-317 (2021)
  4. Synthetic, Cell-Derived, Brain-Derived, and Recombinant β-Amyloid: Modelling Alzheimer's Disease for Research and Drug Development. Varshavskaya KB, Mitkevich VA, Makarov AA, Barykin EP. Int J Mol Sci 23 15036 (2022)
  5. MicroED for the study of protein-ligand interactions and the potential for drug discovery. Clark LJ, Bu G, Nannenga BL, Gonen T. Nat Rev Chem 5 853-858 (2021)
  6. Role of posttranslational modifications in memory and cognitive impairments caused by neonatal sevoflurane exposure. Jiang Y, Zhou Y, Tan S, Xu C, Ma J. Front Pharmacol 14 1113345 (2023)

Articles citing this publication (19)