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.

钙/钙调蛋白依赖性蛋白丝氨酸激酶（CASK）是神经元内囊泡运输和释放的关键因素。但是，它的确切作用，特别是在非神经系统中的作用，还不完全清楚。我们报告说，CASK是胰岛素分泌的重要调节剂。小鼠胰岛/β细胞中的CASK耗竭可大大减少胰岛素分泌和囊泡对接/融合。CASK与Mint1和Munc18-1形成三元复合物，该事件受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表现出独特的“鞭状”结构，紧密围绕CASK-CaMK结构域包裹，该结构域包含两个疏水相互作用位点。当由CASK绑定触发时，Mint1调节复合体的装配。进一步的研究表明，CASK-Mint1结合对于三元复合物的形成至关重要，从而控制Munc18-1膜的定位和胰岛素的分泌。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。