CASK forms an evolutionarily conserved tripartite complex with Mint1 and Veli critical for neuronal synaptic transmission and cell polarity. The CASK CaM kinase (CaMK) domain, in addition to interacting with Mint1, can also bind to many different target proteins, although the mechanism governing CASK-CaMK/target interaction selectivity is unclear. Here, we demonstrate that an extended sequence in the N-terminal unstructured region of Mint1 binds to CASK-CaMK with a dissociation constant of ∼7.5 nM. The high-resolution crystal structure of CASK-CaMK in complex with this Mint1 fragment reveals that the C-lobe of CASK-CaMK binds to a short sequence common to known CaMK targets and the N-lobe of CaMK engages an α helix that is unique to Mint1. Biochemical experiments together with structural analysis reveal that the CASK and Mint1 interaction is not regulated by Ca²⁺/CaM. The CASK/Mint1 complex structure provides mechanistic explanations for several CASK mutations identified in patients with brain disorders and cancers.

CASK与Mint1和Veli形成对神经​​元突触传递和细胞极性至关重要的进化保守的三方复合物。尽管尚不清楚CASK-CaMK /靶相互作用的选择性机制，但CASK CaM激酶（CaMK）结构域除与Mint1相互作用外，还可与许多不同的靶蛋白结合。在这里，我们证明了Mint1的N末端非结构化区域中的扩展序列以〜7.5 nM的解离常数与CASK-CaMK结合。与该Mint1片段复合的CASK-CaMK的高分辨率晶体结构表明，CASK-CaMK的C瓣与已知CaMK靶标共有的短序列结合，而CaMK的N瓣与一个独特的α螺旋结合给Mint1。²⁺ / CaM。CASK / Mint1复杂结构为在患有脑疾病和癌症的患者中鉴定出的几种CASK突变提供了机理解释。