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Modulation of the Activity of the Insulin-Degrading Enzyme by Aβ Peptides

  • Merc M. Kemeh
    Merc M. Kemeh
    Gustaf H. Carlson School of Chemistry and Biochemistry, Clark University, Worcester, Massachusetts 01610, United States
    More by Merc M. Kemeh
  •  and 
  • Noel D. Lazo*
    Noel D. Lazo
    Gustaf H. Carlson School of Chemistry and Biochemistry, Clark University, Worcester, Massachusetts 01610, United States
    *Email: [email protected]
    More by Noel D. Lazo
Cite this: ACS Chem. Neurosci. 2023, 14, 16, 2935–2943
Publication Date (Web):July 27, 2023
https://doi.org/10.1021/acschemneuro.3c00384
Copyright © 2023 American Chemical Society

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    Abstract

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    The insulin-degrading enzyme (IDE) is an evolutionarily conserved protease implicated in the degradation of insulin and amyloidogenic peptides. Most of the biochemical and biophysical characterization of IDE’s catalytic activity has been conducted using solutions containing a single substrate, i.e., insulin or Aβ(1–40). IDE’s activity toward a particular substrate, however, is likely to be influenced by the presence of other substrates. Here, we show by a kinetic assay based on insulin’s helical circular dichroic signal and MALDI TOF mass spectrometry that Aβ peptides modulate IDE’s activity toward insulin in opposing ways. Aβ(1–40) enhances IDE-dependent degradation of insulin, whereas Aβ(pyroE3–42), the most pathogenic pyroglutamate-modified Aβ peptide in AD, inhibits IDE’s activity. Intriguingly, Aβ(pyroE3–42) also inhibits IDE’s ability to degrade Aβ(1–40). Together, our results implicate Aβ peptides in the abnormal catabolism of IDE’s key substrates.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acschemneuro.3c00384.

    • Steady-state kinetic parameters for the degradation of insulin by IDE in the absence and presence of Aβ peptides determined from Michaelis–Menten and Lineweaver–Burk plots, MALDI-TOF mass spectra of IDE-dependent degradation of insulin and corresponding table of observed and theoretical masses of insulin fragments, cleavage sites in insulin identified by MALDI-TOF mass spectrometry, MALDI-TOF mass spectra of IDE-dependent degradation of Aβ(1–40) and corresponding table of observed and theoretical masses of Aβ(1–40) fragments, MALDI-TOF mass spectra of IDE-dependent degradation of Aβ(pyroE3–42), circular dichroic spectra of insulin and insulin + Aβ samples in the absence of IDE, MALDI-TOF mass spectra of IDE-dependent degradation of insulin in the presence of Aβ(1–40) and Aβ(pyroE3–42) and corresponding table of observed and theoretical masses of insulin and Aβ(1–40) fragments, and MALDI-TOF mass spectra of IDE-dependent degradation of Aβ(1–40) in the presence of Aβ(pyroE3–42) (PDF)

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