Structural Insights into Tanc1/2 Autoinhibition and Their Implications for NDD Pathogenesis

Tanc1 and Tanc2 are synaptic scaffold proteins with high structural similarity but distinct expression patterns and functions. Although accumulating evidence points to important divergent roles of Tanc1 and Tanc2 in neural development, the precise molecular mechanisms governing their activity (e.g., autoinhibition and activation) and their pathogenic pathways in neurodevelopmental disorders remain poorly defined. Here, we investigated the molecular basis underlying mouse Tanc1 and Tanc2 autoinhibition, ATP-dependent activation, and disease-mutation induced hyperactivation. Using cryogenic electron microscopy (cryo-EM), we determined the monomeric structures of mouse Tanc1 (215-1452) and Tanc2 (211-1421) in their monomeric states and identified them as STAND/NACHT ATPases, thereby further extend the functional implications of the STAND/NACHT family in neurodevelopmental disorders. And we further revealed their distinct autoinhibitory mechanisms: mTanc1 adopts a closed, inactive conformation stabilized by a 226-231 "lock" segment, whereas mTanc2 dynamically switches between closed and pre-activated states to enable ATP-dependent oligomerization. Biochemical and cellular assays further demonstrated that mTanc2 forms active oligomers with strong ATPase activity and cytoplasmic puncta formation. Notably, neurodevelopmental disorder-associated mTanc2 mutations (R755H, A794V, C890R) further enhanced oligomerization, elevated ATPase activity, and triggered apoptosis, pointing to a hyperactivation-driven pathogenic mechanism. Collectively, these findings reveal distinct autoinhibitory mechanisms within the Tanc family, explain mTanc2's activation propensity, and link its hyperactivation to neuronal dysfunction and neurodevelopmental disorder pathology.