Exploring the Structural Rearrangements of the Human Insulin-Degrading Enzyme through Molecular Dynamics Simulations.

Mariem Ghoula,Gautier Moroy,Nathalie Janel,Anne-Claude Camproux

doi:10.3390/ijms23031746

Abstract

Insulin-degrading enzyme (IDE) is a ubiquitously expressed metallopeptidase that degrades insulin and a large panel of amyloidogenic peptides. IDE is thought to be a potential therapeutic target for type-2 diabetes and neurodegenerative diseases, such as Alzheimer’s disease. IDE catalytic chamber, known as a crypt, is formed, so that peptides can be enclosed and degraded. However, the molecular mechanism of the IDE function and peptide recognition, as well as its conformation changes, remains elusive. Our study elucidates IDE structural changes and explains how IDE conformational dynamics is important to modulate the catalytic cycle of IDE. In this aim, a free-substrate IDE crystallographic structure (PDB ID: 2JG4) was used to model a complete structure of IDE. IDE stability and flexibility were studied through molecular dynamics (MD) simulations to witness IDE conformational dynamics switching from a closed to an open state. The description of IDE structural changes was achieved by analysis of the cavity and its expansion over time. Moreover, the quasi-harmonic analysis of the hinge connecting IDE domains and the angles formed over the simulations gave more insights into IDE shifts. Overall, our results could guide toward the use of different approaches to study IDE with different substrates and inhibitors, while taking into account the conformational states resolved in our study.

Highlights

Published: 3 February 2022Insulin-degrading enzyme (IDE), known as Insulysin, is a zinc protease of theM16 metalloprotease family [1–5]
The transition from the closed to the open conformation is triggered by the achievement of a specific interaction between the IDE catalytic chamber and its substrates
The catalytic activity of IDE is mediated by several structural transitions

Summary

Introduction

Published: 3 February 2022Insulin-degrading enzyme (IDE), known as Insulysin, is a zinc protease of theM16 metalloprotease family [1–5]. Insulin-degrading enzyme (IDE), known as Insulysin, is a zinc protease of the. IDE plays a major role in preventing type II diabetes [6–9] and other diseases, such as Alzheimer’s [10–16]. These characteristics make it one of the most important enzymes in the human body. An important feature of IDE is its large cavity (~15,000 A3 ), where peptides are degraded based on their size, charge distribution, and amyloidogenic nature [19–24]. IDE is a catalytic protein known to switch between a closed and an open state. The transition from the closed to the open conformation is triggered by the achievement of a specific interaction between the IDE catalytic chamber and its substrates.

Methods

Results

Conclusion