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The structure of tyrosine-10 favors ionic conductance of Alzheimer’s disease-associated full-length amyloid-β channels

Author

Listed:
  • Abhijith G. Karkisaval

    (University of California San Diego)

  • Rowan Hassan

    (University of Central Florida)

  • Andrew Nguyen

    (University of California San Diego)

  • Benjamin Balster

    (University of California San Diego)

  • Faisal Abedin

    (University of Central Florida
    Xavier University of Louisiana)

  • Ratnesh Lal

    (University of California San Diego
    University of California San Diego)

  • Suren A. Tatulian

    (University of Central Florida)

Abstract

Amyloid β (Aβ) ion channels destabilize cellular ionic homeostasis, which contributes to neurotoxicity in Alzheimer’s disease. The relative roles of various Aβ isoforms are poorly understood. We use bilayer electrophysiology, AFM imaging, circular dichroism, FTIR and fluorescence spectroscopy to characterize channel activities of four most prevalent Aβ peptides, Aβ1-42, Aβ1-40, and their pyroglutamylated forms (AβpE3-42, AβpE3-40) and correlate them with the peptides’ structural features. Solvent-induced fluorescence splitting of tyrosine-10 is discovered and used to assess the sequestration from the solvent and membrane insertion. Aβ1-42 effectively embeds in lipid membranes, contains large fraction of β-sheet in a β-barrel-like structure, forms multi-subunit pores in membranes, and displays well-defined ion channel features. In contrast, the other peptides are partially solvent-exposed, contain minimal β-sheet structure, form less-ordered assemblies, and produce irregular ionic currents. These findings illuminate the structural basis of Aβ neurotoxicity through membrane permeabilization and may help develop therapies that target Aβ-membrane interactions.

Suggested Citation

  • Abhijith G. Karkisaval & Rowan Hassan & Andrew Nguyen & Benjamin Balster & Faisal Abedin & Ratnesh Lal & Suren A. Tatulian, 2024. "The structure of tyrosine-10 favors ionic conductance of Alzheimer’s disease-associated full-length amyloid-β channels," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-43821-y
    DOI: 10.1038/s41467-023-43821-y
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    1. Sonia Ciudad & Eduard Puig & Thomas Botzanowski & Moeen Meigooni & Andres S. Arango & Jimmy Do & Maxim Mayzel & Mariam Bayoumi & Stéphane Chaignepain & Giovanni Maglia & Sarah Cianferani & Vladislav O, 2020. "Aβ(1-42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
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