A non‐canonical PDZ recognition mechanism underlies the synaptic CTNND2 – MAGI2 complex assembly

The cadherin–catenin complex governs neuronal development and synaptic signaling by linking cell adhesion to cytoskeletal dynamics. CTNND2 (δ‐catenin) is a neuron‐enriched p120 catenin whose C‐terminal PDZ domain‐binding motif (PBM) plays essential roles in dendritic spine morphogenesis and synaptic plasticity; however, its direct postsynaptic binding partner(s) and the structural determinant of binding selectivity remain unclear. Here, we systematically screened major postsynaptic PDZ proteins and identified MAGI2 as a specific, high‐affinity binder that recognizes the CTNND2 PBM exclusively via its PDZ5 domain. The crystal structure of the CTNND2 PBM–MAGI2 PDZ5 complex reveals a previously unrecognized electrostatic contact between D(−3) of the PBM and R1154 of PDZ5 that dictates specificity, explaining why other PDZ domains fail to bind CTNND2 PBM. This atypical PDZ–PBM interaction mode is conserved among p120 catenin family members ARVCF and PKP4, and extends to the classic catenin β‐catenin. Our findings define a non‐canonical PDZ recognition mechanism underlying the CTNND2–MAGI2 synaptic complex, with implications for CTNND2‐related diseases.