Ensemble cryoEM elucidates the mechanism of insulin capture and degradation by human insulin degrading enzyme
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...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2018-03-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/33572 |
| _version_ | 1811252957701734400 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Zhening Zhang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T16:43:36Z |
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| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:43:36Z |
| publishDate | 2018-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-bdf640b40b944a06bfcc72ce62dd40712022-12-22T03:24:41ZengeLife Sciences Publications LtdeLife2050-084X2018-03-01710.7554/eLife.33572Ensemble cryoEM elucidates the mechanism of insulin capture and degradation by human insulin degrading enzymeZhening Zhang0Wenguang G Liang1Lucas J Bailey2Yong Zi Tan3https://orcid.org/0000-0001-6656-6320Hui Wei4Andrew Wang5Mara Farcasanu6Virgil A Woods7Lauren A McCord8David Lee9Weifeng Shang10Rebecca Deprez-Poulain11Benoit Deprez12David R Liu13Akiko Koide14Shohei Koide15Anthony A Kossiakoff16Sheng Li17Bridget Carragher18https://orcid.org/0000-0002-0624-5020Clinton S Potter19https://orcid.org/0000-0003-2394-0831Wei-Jen Tang20https://orcid.org/0000-0002-8267-8995National Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center, New York, United StatesBen-May Institute for Cancer Research, The University of Chicago, Chicago, United StatesDepartment of Biochemistry and Molecular Biology, The University of Chicago, Chicago, United StatesNational Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center, New York, United States; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United StatesNational Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center, New York, United StatesBen-May Institute for Cancer Research, The University of Chicago, Chicago, United StatesBen-May Institute for Cancer Research, The University of Chicago, Chicago, United StatesDepartment of Medicine, University of California, San Diego, La Jolla, United StatesBen-May Institute for Cancer Research, The University of Chicago, Chicago, United StatesDepartment of Medicine, University of California, San Diego, La Jolla, United StatesBioCAT, Argonne National Laboratory, Illinois, United StatesUniv. Lille, INSERM, Institut Pasteur de Lille, Lille, FranceUniv. Lille, INSERM, Institut Pasteur de Lille, Lille, FranceDepartment of Chemistry and Chemical Biology, Harvard University, Cambridge, United StatesPerlmutter Cancer Center, New York University School of Medicine, New York, United States; New York University Langone Medical Center, New York University School of Medicine, New York, United States; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, United StatesPerlmutter Cancer Center, New York University School of Medicine, New York, United States; New York University Langone Medical Center, New York University School of Medicine, New York, United States; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, United StatesDepartment of Biochemistry and Molecular Biology, The University of Chicago, Chicago, United StatesDepartment of Medicine, University of California, San Diego, La Jolla, United StatesNational Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center, New York, United States; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United StatesNational Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center, New York, United States; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United StatesBen-May Institute for Cancer Research, The University of Chicago, Chicago, United StatesInsulin 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.https://elifesciences.org/articles/33572insulinamyloid peptideinsulin degrading enzymeproteostasiscryoEMintegrative structural biology |
| spellingShingle | 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 Ensemble cryoEM elucidates the mechanism of insulin capture and degradation by human insulin degrading enzyme eLife insulin amyloid peptide insulin degrading enzyme proteostasis cryoEM integrative structural biology |
| title | Ensemble cryoEM elucidates the mechanism of insulin capture and degradation by human insulin degrading enzyme |
| title_full | Ensemble cryoEM elucidates the mechanism of insulin capture and degradation by human insulin degrading enzyme |
| title_fullStr | Ensemble cryoEM elucidates the mechanism of insulin capture and degradation by human insulin degrading enzyme |
| title_full_unstemmed | Ensemble cryoEM elucidates the mechanism of insulin capture and degradation by human insulin degrading enzyme |
| title_short | Ensemble cryoEM elucidates the mechanism of insulin capture and degradation by human insulin degrading enzyme |
| title_sort | ensemble cryoem elucidates the mechanism of insulin capture and degradation by human insulin degrading enzyme |
| topic | insulin amyloid peptide insulin degrading enzyme proteostasis cryoEM integrative structural biology |
| url | https://elifesciences.org/articles/33572 |
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