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Hetero-oligomeric Amyloid Assembly and Mechanism: Prion Fragment PrP(106–126) Catalyzes the Islet Amyloid Polypeptide β-Hairpin

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    Hetero-oligomeric Amyloid Assembly and Mechanism: Prion Fragment PrP(106–126) Catalyzes the Islet Amyloid Polypeptide β-Hairpin
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    • Alexandre I. Ilitchev
      Alexandre I. Ilitchev
      Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
      More by Alexandre I. Ilitchev
      Orcidhttp://orcid.org/0000-0002-1503-4217
    • Maxwell J. Giammona
      Maxwell J. Giammona
      Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
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    • Carina Olivas
      Carina Olivas
      Department of Chemistry and Biochemistry, Rowan University, Glassboro, New Jersey 08028, United States
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    • Sarah L. Claud
      Sarah L. Claud
      Department of Chemistry, Westmont College, Santa Barbara, California 93108, United States
      More by Sarah L. Claud
    • Kristi L. Lazar Cantrell
      Kristi L. Lazar Cantrell
      Department of Chemistry, Westmont College, Santa Barbara, California 93108, United States
      More by Kristi L. Lazar Cantrell
    • Chun Wu
      Chun Wu
      Department of Chemistry and Biochemistry, Rowan University, Glassboro, New Jersey 08028, United States
      More by Chun Wu
      Orcidhttp://orcid.org/0000-0002-0176-3873
    • Steven K. Buratto
      Steven K. Buratto
      Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
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    • Michael T. Bowers*
      Michael T. Bowers
      Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
      *[email protected]
      More by Michael T. Bowers
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    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2018, 140, 30, 9685–9695
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    https://doi.org/10.1021/jacs.8b05925
    Published July 10, 2018
    Copyright © 2018 American Chemical Society
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    Abstract

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    Protein aggregation is typically attributed to the association of homologous amino acid sequences between monomers of the same protein. Coaggregation of heterogeneous peptide species can occur, however, and is implicated in the proliferation of seemingly unrelated protein diseases in the body. The prion protein fragment (PrP106–126) and human islet amyloid polypeptide (hIAPP) serve as an interesting model of nonhomologous protein assembly as they coaggregate, despite a lack of sequence homology. We have applied ion-mobility mass spectrometry, atomic force microscopy, circular dichroism, and high-level molecular modeling to elucidate this important assembly process. We found that the prion fragment not only forms pervasive hetero-oligomeric aggregates with hIAPP but also promotes the transition of hIAPP into its amyloidogenic β-hairpin conformation. Further, when PrP106–126 was combined with non-amyloidogenic rIAPP, the two formed nearly identical hetero-oligomers to those seen with hIAPP, despite rIAPP containing β-sheet breaking proline substitutions. Additionally, while rIAPP does not natively form the amyloidogenic β-hairpin structure, it did so in the presence of PrP106–126 and underwent a conformational transition to β-sheet in solution. We also find that PrP106–126 forms hetero-oligomers with the IAPP8–20 fragment but not with the “aggregation hot spot” IAPP20–29 fragment. PrP106–126 apparently induces IAPP into a β-hairpin structure within the PrP:IAPP heterodimer complex and then, through ligand exchange, catalytically creates the amyloidogenic β-hairpin dimer of IAPP in significantly greater abundance than IAPP does on its own. This is a new mechanistic model that provides a critical foundation for the detailed study of hetero-oligomerization and prion-like proliferation in amyloid systems.

    Copyright © 2018 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.8b05925.

    • Ion-mobility experimental details, atomic force microscopy analysis details, replica exchange molecular dynamics simulation details, initial monomer structures of REMD simulations, AFM particle height analysis, comparative mass spectra of PrP106–126 with hIAPP fragments, REMD simulation results, solvent comparison for hIAPP–PrP106–126 mixtures, injection energy studies of 1/+4 hIAPP in hIAPP–PrP106–126 mixtures, and comparative arrival time distributions of 1:1 PrP106–126–hIAPP8–20 hetero-oligomers at pH = 7.5 and 4.5 (PDF)

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    Cite this: J. Am. Chem. Soc. 2018, 140, 30, 9685–9695
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jacs.8b05925
    Published July 10, 2018
    Copyright © 2018 American Chemical Society
    Request reuse permissions

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