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CASK modulates the assembly and function of the Mint1/Munc18-1 complex to regulate insulin secretion

Calcium/calmodulin-dependent protein serine kinase (CASK) is a key player in vesicle transport and release in neurons. However, its precise role, particularly in nonneuronal systems, is incompletely understood. We report that CASK functions as an important regulator of insulin secretion. CASK deplet...

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Autores principales: Zhang, Zhe, Li, Wei, Yang, Guang, Lu, Xuefeng, Qi, Xin, Wang, Shuting, Cao, Can, Zhang, Peng, Ren, Jinqi, Zhao, Jiaxu, Zhang, Junyi, Hong, Sheng, Tan, Yan, Burchfield, James, Yu, Yang, Xu, Tao, Yao, Xuebiao, James, David, Feng, Wei, Chen, Zhengjun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Singapore 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736295/
https://www.ncbi.nlm.nih.gov/pubmed/33318489
http://dx.doi.org/10.1038/s41421-020-00216-3
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author Zhang, Zhe
Li, Wei
Yang, Guang
Lu, Xuefeng
Qi, Xin
Wang, Shuting
Cao, Can
Zhang, Peng
Ren, Jinqi
Zhao, Jiaxu
Zhang, Junyi
Hong, Sheng
Tan, Yan
Burchfield, James
Yu, Yang
Xu, Tao
Yao, Xuebiao
James, David
Feng, Wei
Chen, Zhengjun
author_facet Zhang, Zhe
Li, Wei
Yang, Guang
Lu, Xuefeng
Qi, Xin
Wang, Shuting
Cao, Can
Zhang, Peng
Ren, Jinqi
Zhao, Jiaxu
Zhang, Junyi
Hong, Sheng
Tan, Yan
Burchfield, James
Yu, Yang
Xu, Tao
Yao, Xuebiao
James, David
Feng, Wei
Chen, Zhengjun
author_sort Zhang, Zhe
collection PubMed
description Calcium/calmodulin-dependent protein serine kinase (CASK) is a key player in vesicle transport and release in neurons. However, its precise role, particularly in nonneuronal systems, is incompletely understood. We report that CASK functions as an important regulator of insulin secretion. CASK depletion in mouse islets/β cells substantially reduces insulin secretion and vesicle docking/fusion. CASK forms a ternary complex with Mint1 and Munc18-1, and this event is regulated by glucose stimulation in β cells. The crystal structure of the CASK/Mint1 complex demonstrates that Mint1 exhibits a unique “whip”-like structure that wraps tightly around the CASK-CaMK domain, which contains dual hydrophobic interaction sites. When triggered by CASK binding, Mint1 modulates the assembly of the complex. Further investigation revealed that CASK-Mint1 binding is critical for ternary complex formation, thereby controlling Munc18-1 membrane localization and insulin secretion. Our work illustrates the distinctive molecular basis underlying CASK/Mint1/Munc18-1 complex formation and reveals the importance of the CASK-Mint1-Munc18 signaling axis in insulin secretion.
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spelling pubmed-77362952020-12-21 CASK modulates the assembly and function of the Mint1/Munc18-1 complex to regulate insulin secretion Zhang, Zhe Li, Wei Yang, Guang Lu, Xuefeng Qi, Xin Wang, Shuting Cao, Can Zhang, Peng Ren, Jinqi Zhao, Jiaxu Zhang, Junyi Hong, Sheng Tan, Yan Burchfield, James Yu, Yang Xu, Tao Yao, Xuebiao James, David Feng, Wei Chen, Zhengjun Cell Discov Article Calcium/calmodulin-dependent protein serine kinase (CASK) is a key player in vesicle transport and release in neurons. However, its precise role, particularly in nonneuronal systems, is incompletely understood. We report that CASK functions as an important regulator of insulin secretion. CASK depletion in mouse islets/β cells substantially reduces insulin secretion and vesicle docking/fusion. CASK forms a ternary complex with Mint1 and Munc18-1, and this event is regulated by glucose stimulation in β cells. The crystal structure of the CASK/Mint1 complex demonstrates that Mint1 exhibits a unique “whip”-like structure that wraps tightly around the CASK-CaMK domain, which contains dual hydrophobic interaction sites. When triggered by CASK binding, Mint1 modulates the assembly of the complex. Further investigation revealed that CASK-Mint1 binding is critical for ternary complex formation, thereby controlling Munc18-1 membrane localization and insulin secretion. Our work illustrates the distinctive molecular basis underlying CASK/Mint1/Munc18-1 complex formation and reveals the importance of the CASK-Mint1-Munc18 signaling axis in insulin secretion. Springer Singapore 2020-12-15 /pmc/articles/PMC7736295/ /pubmed/33318489 http://dx.doi.org/10.1038/s41421-020-00216-3 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Zhang, Zhe
Li, Wei
Yang, Guang
Lu, Xuefeng
Qi, Xin
Wang, Shuting
Cao, Can
Zhang, Peng
Ren, Jinqi
Zhao, Jiaxu
Zhang, Junyi
Hong, Sheng
Tan, Yan
Burchfield, James
Yu, Yang
Xu, Tao
Yao, Xuebiao
James, David
Feng, Wei
Chen, Zhengjun
CASK modulates the assembly and function of the Mint1/Munc18-1 complex to regulate insulin secretion
title CASK modulates the assembly and function of the Mint1/Munc18-1 complex to regulate insulin secretion
title_full CASK modulates the assembly and function of the Mint1/Munc18-1 complex to regulate insulin secretion
title_fullStr CASK modulates the assembly and function of the Mint1/Munc18-1 complex to regulate insulin secretion
title_full_unstemmed CASK modulates the assembly and function of the Mint1/Munc18-1 complex to regulate insulin secretion
title_short CASK modulates the assembly and function of the Mint1/Munc18-1 complex to regulate insulin secretion
title_sort cask modulates the assembly and function of the mint1/munc18-1 complex to regulate insulin secretion
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736295/
https://www.ncbi.nlm.nih.gov/pubmed/33318489
http://dx.doi.org/10.1038/s41421-020-00216-3
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