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

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Warmack RA, Boyer DR, Zee CT, Richards LS, Sawaya MR, Cascio D, Gonen T, Eisenberg DS, Clarke SG
OpenAccess logo Nat Commun 10 3357 (2019)
Cited: 27 times
EuropePMC logo PMID: 31350392

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)

  1. Cryo-EM structure and inhibitor design of human IAPP (amylin) fibrils. Cao Q, Boyer DR, Sawaya MR, Ge P, Eisenberg DS. Nat Struct Mol Biol 27 653-659 (2020)


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)

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  1. Cryo-EM structures of amyloid-β 42 filaments from human brains. Yang Y, Arseni D, Zhang W, Zhang W, Huang M, Lövestam S, Schweighauser M, Kotecha A, Murzin AG, Peak-Chew SY, Macdonald J, Lavenir I, Garringer HJ, Gelpi E, Newell KL, Kovacs GG, Vidal R, Ghetti B, Ryskeldi-Falcon B, Scheres SHW, Goedert M. Science 375 167-172 (2022)
  2. The α-synuclein hereditary mutation E46K unlocks a more stable, pathogenic fibril structure. Boyer DR, Li B, Sun C, Fan W, Zhou K, Hughes MP, Sawaya MR, Jiang L, Eisenberg DS. Proc Natl Acad Sci U S A 117 3592-3602 (2020)
  3. Cryo-EM structures of hIAPP fibrils seeded by patient-extracted fibrils reveal new polymorphs and conserved fibril cores. Cao Q, Boyer DR, Sawaya MR, Abskharon R, Saelices L, Nguyen BA, Lu J, Murray KA, Kandeel F, Eisenberg DS. Nat Struct Mol Biol 28 724-730 (2021)
  4. Beam-sensitive metal-organic framework structure determination by microcrystal electron diffraction. Banihashemi F, Bu G, Thaker A, Williams D, Lin JYS, Nannenga BL. Ultramicroscopy 216 113048 (2020)
  5. Chiral Selectivity of Secondary Nucleation in Amyloid Fibril Propagation. Törnquist M, Linse S. Angew Chem Int Ed Engl 60 24008-24011 (2021)
  6. Computational Investigation of Gantenerumab and Crenezumab Recognition of Aβ Fibrils in Alzheimer's Disease Brain Tissue. Chen Y, Wei G, Zhao J, Nussinov R, Ma B. ACS Chem Neurosci 11 3233-3244 (2020)
  7. Recent Developments Toward Integrated Metabolomics Technologies (UHPLC-MS-SPE-NMR and MicroED) for Higher-Throughput Confident Metabolite Identifications. Ghosh R, Bu G, Nannenga BL, Sumner LW. Front Mol Biosci 8 720955 (2021)
  8. Chiral Interface of Amyloid Beta (Aβ): Relevance to Protein Aging, Aggregation and Neurodegeneration. Dyakin VV, Wisniewski TM, Lajtha A. Symmetry (Basel) 12 585 (2020)
  9. Rapid Structural Analysis of a Synthetic Non-canonical Amino Acid by Microcrystal Electron Diffraction. Gleason PR, Nannenga BL, Mills JH. Front Mol Biosci 7 609999 (2020)
  10. An Unusually Rapid Protein Backbone Modification Stabilizes the Essential Bacterial Enzyme MurA. Zhang T, Hansen K, Politis A, Müller MM. Biochemistry 59 3683-3695 (2020)
  11. MicroED Sample Preparation and Data Collection For Protein Crystals. Bu G, Nannenga BL. Methods Mol Biol 2215 287-297 (2021)
  12. Fragment-Based Ab Initio Phasing of Peptidic Nanocrystals by MicroED. Richards LS, Flores MD, Millán C, Glynn C, Zee CT, Sawaya MR, Gallagher-Jones M, Borges RJ, Usón I, Rodriguez JA. ACS Bio Med Chem Au 3 201-210 (2023)
  13. l-Isoaspartyl Methyltransferase Deficiency in Zebrafish Leads to Impaired Calcium Signaling in the Brain. Soliman R, Cordero-Maldonado ML, Martins TG, Moein M, Conrotte JF, Warmack RA, Skupin A, Crawford AD, Clarke SG, Linster CL. Front Genet 11 612343 (2020)
  14. A Hybrid Structural Method for Investigating Low Molecular Weight Oligomeric Structures of Amyloid Beta. Gupta S, Raskatov JA, Ralston CY. Chembiochem 23 e202200333 (2022)
  15. Biological effects of the loss of homochirality in a multicellular organism. Banreti A, Bhattacharya S, Wien F, Matsuo K, Réfrégiers M, Meinert C, Meierhenrich U, Hudry B, Thompson D, Noselli S. Nat Commun 13 7059 (2022)
  16. PCMT1 regulates the migration, invasion, and apoptosis of prostate cancer through modulating the PI3K/AKT/GSK-3β pathway. Zhong J, Yuan C, Liu L, Du Y, Hui Y, Chen Z, Diao C, Yang R, Liu G, Liu X. Aging (Albany NY) 15 11654-11671 (2023)
  17. Probing effects of site-specific aspartic acid isomerization on structure and stability of GB1 through chemical protein synthesis. Heath SL, Guseman AJ, Gronenborn AM, Horne WS. Protein Sci 33 e4883 (2024)
  18. True molecular conformation and structure determination by three-dimensional electron diffraction of PAH by-products potentially useful for electronic applications. Andrusenko I, Hall CL, Mugnaioli E, Potticary J, Hall SR, Schmidt W, Gao S, Zhao K, Marom N, Gemmi M. IUCrJ 10 131-142 (2023)
  19. Simulations on the dual effects of flavonoids as suppressors of Aβ42 fibrillogenesis and destabilizers of mature fibrils. Gargari SA, Barzegar A. Sci Rep 10 16636 (2020)


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