Ensemble cryoEM elucidates the mechanism of insulin capture and degradation by human insulin degrading enzyme
Abstract
Insulin degrading enzyme (IDE) plays key roles in degrading peptides vital in type two diabetes, Alzheimer's, inflammation, and other human diseases. However, the process through which IDE recognizes peptides that tend to form amyloid fibrils remained unsolved. We used cryoEM to understand both the apo- and insulin-bound dimeric IDE states, revealing that IDE displays a large opening between the homologous ~55 kDa N- and C-terminal halves to allow selective substrate capture based on size and charge complementarity. We also used cryoEM, X-ray crystallography, SAXS, and HDX-MS to elucidate the molecular basis of how amyloidogenic peptides stabilize the disordered IDE catalytic cleft, thereby inducing selective degradation by substrate-assisted catalysis. Furthermore, our insulin-bound IDE structures explain how IDE processively degrades insulin by stochastically cutting either chain without breaking disulfide bonds. Together, our studies provide a mechanism for how IDE selectively degrades amyloidogenic peptides and offers structural insights for developing IDE-based therapies.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 29, 2018
- Source ID
- 10.7554/elife.33572
Entities
People
- Akiko Koide
- Andrew Wang
- Anthony A. Kossiakoff
- Benoit Deprez
- Bridget Carragher
- Clinton S Potter
- David Lee
- David R. Liu
- Hui Wei
- Lauren A Mccord
- Lucas J Bailey
- Mara Farcasanu
- Rebecca Deprez-poulain
- Sheng Li
- Shohei Koide
- Virgil A Woods
- Wei-Jen Tang
- Weifeng Shang
- Wenguang G Liang
- Yong Zi Tan
- Zhening Zhang
Organizations
- Agency for Science, Technology and Research
- Biocat
- Columbia University
- Defense Advanced Research Projects Agency
- Grossman School of Medicine
- Harvard University
- Howard Hughes Medical Institute
- National Institutes of Health
- New York University
- Simons Foundation
- University of California, San Diego
- University of Chicago