Abstract
The emergence of genes implicated across multiple comorbid neurologic disorders allows to identify shared underlying molecular pathways. Recently, investigation of patients with diverse neurologic disorders found TANC1 and TANC2 as possible candidate disease genes. While the TANC proteins have been reported as postsynaptic scaffolds influencing synaptic spines and excitatory synapse strength, their molecular functions remain unknown. Here, we conducted a comprehensive in silico analysis of the TANC protein family to characterize their molecular role and understand possible neurobiological consequences of their disruption. The known Ankyrin and tetratricopeptide repeat (TPR) domains have been modeled. The newly predicted N-terminal ATPase domain may function as a regulated molecular switch for downstream signaling. Several putative conserved protein binding motifs allowed to extend the TANC interaction network. Interestingly, we highlighted connections with different signaling pathways converging to modulate neuronal activity. Beyond a known role for TANC family members in the glutamate receptor pathway, they seem linked to planar cell polarity signaling, Hippo pathway, and cilium assembly. This suggests an important role in neuron projection, extension and differentiation.
Highlights
Neurodevelopmental disorders (NDDs) are common conditions including clinically and genetically heterogeneous diseases, such as intellectual disability (ID), autism spectrum disorder (ASD), and epilepsy[1]
A P-loop ATPase domain was first observed at the N-terminus of the rolling pebbles orthologs of TANC proteins by Leipe and colleagues using sequence profile analysis and sequence-based structure prediction to define the novel class of STAND (Signal Transducing ATPase with Numerous Domains) nucleoside triphosphate hydrolase (NTPase)[13]
Known interactors for both TANC proteins were downloaded from BioGrid[29], IntAct[30], and STRING31
Summary
Neurodevelopmental disorders (NDDs) are common conditions including clinically and genetically heterogeneous diseases, such as intellectual disability (ID), autism spectrum disorder (ASD), and epilepsy[1]. Scaffold proteins seem to play a critical role in glutamatergic neurotransmission, organizing different components of glutamate receptor complexes at post-synaptic densities (PSDs) and determining synaptic strength and plasticity[7]. TANC1 interacts with PSD95, one of the most important and well characterized scaffold proteins, as well as additional postsynaptic proteins including glutamate receptors[8, 9]. Available experimental evidence suggests an important role for these proteins in neuronal development, little is still known about the pathogenic mechanisms involved[8]. Even though the nucleotide binding activity of the TANC P-loop domain and its functional role have to be demonstrated, this particular multi-domain architecture suggests at least a mechanistic similarity in molecular functions for TANC protein, combining a regulatory molecular switch with scaffold properties to assembly highly dynamic protein complexes. Predicted and collected data highlight TANC involvement in orchestrating different neuronal signaling pathways, which may be implicated in the pathogenesis of diverse NDDs
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