AI Article Synopsis
- Insulin degrading enzyme (IDE) is crucial for breaking down peptides linked to several diseases, including type 2 diabetes and Alzheimer's, but how it identifies certain harmful peptides was unclear.
- Using techniques like cryoEM and X-ray crystallography, the researchers discovered that IDE has a sizeable opening that allows it to selectively capture substrates based on their size and charge.
- The study provides insights into how IDE stabilizes and degrades amyloidogenic peptides and insulin, potentially guiding future therapies targeting IDE.
Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910022 | PMC |
| http://dx.doi.org/10.7554/eLife.33572 | DOI Listing |
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