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-Structure paper
タイトル | Ensemble cryoEM elucidates the mechanism of insulin capture and degradation by human insulin degrading enzyme. |
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ジャーナル・号・ページ | Elife, Vol. 7, Year 2018 |
掲載日 | 2018年3月29日 |
著者 | Zhening Zhang / Wenguang G Liang / Lucas J Bailey / Yong Zi Tan / Hui Wei / Andrew Wang / Mara Farcasanu / Virgil A Woods / Lauren A McCord / David Lee / Weifeng Shang / Rebecca Deprez-Poulain / Benoit Deprez / David R Liu / Akiko Koide / Shohei Koide / Anthony A Kossiakoff / Sheng Li / Bridget Carragher / Clinton S Potter / Wei-Jen Tang / |
PubMed 要旨 | 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 ...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. |
リンク | Elife / PubMed:29596046 / PubMed Central |
手法 | EM (単粒子) / X線回折 |
解像度 | 3.7 - 7.2 Å |
構造データ | EMDB-7041, PDB-6b3q, PDB-6bfc: EMDB-7062, PDB-6b70: EMDB-7065: Cryo-EM structure of human insulin degrading enzyme in complex with insulin EMDB-7066: Cryo-EM structure of human insulin degrading enzyme in complex with insulin EMDB-7091, PDB-6bf7: EMDB-7092, PDB-6bf8: EMDB-7093, PDB-6bf9: PDB-5wob: |
化合物 | ChemComp-ZN: |
由来 |
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キーワード | HYDROLASE / complex / HYDROLASE/HORMONE / IDE / insulin degrading enzyme / amyloid beta / HYDROLASE-HORMONE complex / HYDROLASE/IMMUNE SYSTEM/HORMONE / BIOSYNTHETIC PROTEIN / HYDROLASE-IMMUNE SYSTEM-HORMONE complex / HYDROLASE/IMMUNE SYSTEM / HYDROLASE-IMMUNE SYSTEM complex / HORMONE |