025-22 – How do Autism Spectrum Disorder (ASD) associated mutations affect SHANK3 stability and interactions?

Autism Spectrum Disorder (ASD) is a complex, heterogeneous, neuropsychiatric disorder. SHANK3 encodes a multi-domain scaffolding protein expressed in the postsynaptic density (PSD) of excitable glutamatergic neurons within the brain. Shank3 domains and their multiple interactors are integral in linking receptors at the postsynaptic membrane to the actin cytoskeleton. Many ASD mutations have been identified in SHANK family proteins (SHANK 1, 2, and 3); particularly within the N terminal region of SHANK3 which includes SPN and Ankyrin repeat (Ank) domains.
Our research has shown that Shank3 function is dependent on the stability and the interactions between SPN and Ank domains. These properties are affected by ASD mutations. In this presentation, we define the areas responsible for the instability of the N terminal Shank3 domains and investigate their evolutional conservation. We relate ASD mutations to Shank3 stability and define the effect of these mutations on interactions with Shank3 ligands.