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

Area of Science:

• Neuroscience
• Molecular Biology
• Structural Biology

Background:

• Tanc1 and Tanc2 are synaptic scaffold proteins with similar structures but different roles in neural development.
• Their precise activation mechanisms and roles in neurodevelopmental disorders are not well understood.

Purpose of the Study:

• To investigate the molecular basis of mouse Tanc1 and Tanc2 autoinhibition, ATP-dependent activation, and disease-mutation induced hyperactivation.
• To elucidate the structural and functional differences between Tanc1 and Tanc2.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine monomeric structures of mouse Tanc1 and Tanc2.
• Biochemical and cellular assays to analyze protein activity and oligomerization.

Main Results:

• Tanc1 and Tanc2 were identified as STAND/NACHT ATPases.
• Distinct autoinhibitory mechanisms were revealed: mTanc1 is locked in an inactive state, while mTanc2 dynamically switches between states for oligomerization.
• mTanc2 forms active oligomers with high ATPase activity.
• Disease-associated mTanc2 mutations enhance oligomerization, increase ATPase activity, and induce apoptosis, suggesting a hyperactivation-driven pathogenic mechanism.

Conclusions:

• The study reveals distinct autoinhibition mechanisms in the Tanc protein family.
• It explains mTanc2's propensity for activation and links its hyperactivation to neuronal dysfunction and neurodevelopmental disorder pathology.