Gustaf H. Carlson School of Chemistry and Biochemistry, Clark University, Worcester, Massachusetts 01610, United States.
ACS Chem Neurosci. 2023 Aug 16;14(16):2935-2943. doi: 10.1021/acschemneuro.3c00384. Epub 2023 Jul 27.
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.
胰岛素降解酶（IDE）是一种进化上保守的蛋白酶，参与胰岛素和淀粉样肽的降解。大多数关于 IDE 催化活性的生化和生物物理特性的研究都是使用含有单一底物的溶液进行的，即胰岛素或 Aβ（1-40）。然而，IDE 对特定底物的活性可能受到其他底物的影响。在这里，我们通过基于胰岛素螺旋圆二色性信号和 MALDI-TOF 质谱的动力学测定表明，Aβ 肽以相反的方式调节 IDE 对胰岛素的活性。Aβ（1-40）增强了 IDE 依赖性胰岛素降解，而 AD 中最具致病性的焦谷氨酸修饰 Aβ 肽 Aβ（pyroE3-42）抑制了 IDE 的活性。有趣的是，Aβ（pyroE3-42）也抑制了 IDE 降解 Aβ（1-40）的能力。总之，我们的结果表明 Aβ 肽参与了 IDE 关键底物的异常代谢。
