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CASK调节Mint1/Munc18-1复合物的组装和功能，以调节胰岛素分泌。

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

作者信息

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

机构信息

State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China.

National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.

出版信息

Cell Discov. 2020 Dec 15;6(1):92. doi: 10.1038/s41421-020-00216-3.

DOI:10.1038/s41421-020-00216-3
PMID:33318489
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7736295/
Abstract

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.

摘要

钙/钙调蛋白依赖性蛋白丝氨酸激酶（CASK）是神经元中囊泡运输和释放的关键参与者。然而，其确切作用，尤其是在非神经元系统中的作用，尚未完全明确。我们报告称，CASK作为胰岛素分泌的重要调节因子发挥作用。小鼠胰岛/β细胞中CASK的缺失显著降低了胰岛素分泌以及囊泡对接/融合。CASK与Mint1和Munc18-1形成三元复合物，并且这一过程受β细胞中葡萄糖刺激的调节。CASK/Mint1复合物的晶体结构表明，Mint1呈现出独特的“鞭状”结构，紧密缠绕在包含两个疏水相互作用位点的CASK-CaMK结构域周围。当受到CASK结合触发时，Mint1调节复合物的组装。进一步研究表明，CASK-Mint1结合对于三元复合物的形成至关重要，从而控制Munc18-1的膜定位和胰岛素分泌。我们的工作阐明了CASK/Mint1/Munc18-1复合物形成的独特分子基础，并揭示了CASK-Mint1-Munc18信号轴在胰岛素分泌中的重要性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cb3c/7736295/27cc0d46938a/41421_2020_216_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cb3c/7736295/0b5127dfc3de/41421_2020_216_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cb3c/7736295/a13cfceb823f/41421_2020_216_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cb3c/7736295/e7da2e9531db/41421_2020_216_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cb3c/7736295/c86ea599b27d/41421_2020_216_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cb3c/7736295/889984f46bff/41421_2020_216_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cb3c/7736295/9412365d73d2/41421_2020_216_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cb3c/7736295/0896bd9bedde/41421_2020_216_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cb3c/7736295/27cc0d46938a/41421_2020_216_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cb3c/7736295/0b5127dfc3de/41421_2020_216_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cb3c/7736295/a13cfceb823f/41421_2020_216_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cb3c/7736295/e7da2e9531db/41421_2020_216_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cb3c/7736295/c86ea599b27d/41421_2020_216_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cb3c/7736295/889984f46bff/41421_2020_216_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cb3c/7736295/9412365d73d2/41421_2020_216_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cb3c/7736295/0896bd9bedde/41421_2020_216_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cb3c/7736295/27cc0d46938a/41421_2020_216_Fig8_HTML.jpg

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