CASK is a unique scaffold protein in the synapse system. It links numerous proteins to the pre- or post-synaptic region and is critical to the homeostasis of synaptic vesicles. The N-terminus of CASK is a calcium/calmodulin-dependent protein kinase (CAMK) domain, which has diverse functions and interacts with downstream proteins to form a scaffold platform. Caskin1 is one of the brain-specific adaptor proteins of CASK. Here we crystalized the Caskin1_CASK interaction domain (CID) and CASK_CAMK. Comprehensive X-ray crystallographic study of Caskin1_CID/CASK_CAMK complex and following biochemical/ cell biology experiments uncovered the interaction codes governing CASK_CAMK and its binding partners. Previous studies showed that CASK_CAMK domain interacts with Caskin1 CID domain with relatively low affinity. In this study, we re-visit this interaction by re-mapping the interaction boundary and solving their complex structure. Based on the structure, we systematically compared the interactions between CASK_CAMK and other binding partners. Our results showed that CAMK domain occupy the CID peptide by using its C-lobe groove (between the α1 and α2) and there is a highly conserved signature motif (ζ-x-ψ-W-ψ-x-R) in the CID domain, where ζ is acidic side chain containing residues, x is any amino acid residue, ψ is hydrophobic residues, W is for tryptophan, and R is arginine. These findings allowed us to identify several new potential cytoplasmic binding partners for CASK_CAMK.