036-23 – SPN-SPN Self-Associations in Shank3: Unveiling Molecular Mechanisms in Autism Spectrum Conditions

Autism spectrum conditions (ASCs) are complex, heterogeneous neurodevelopmental conditions. Shank3, a synaptic scaffold protein and actin regulator, is expressed within excitable glutamatergic neurons and has been closely linked to ASC in genomic studies. ASC mutations within the Shank3 N-terminus region consisting of the SPN and the ankyrin repeat domain (ARR) have resulted in decreased intramolecular interaction in vitro. However, the significance of this disruption and its contribution to the development of autism pathology remain unclear.

In this study, we aimed to investigate the self-association of the SPN domain and its potential implications for the molecular mechanisms underlying ASCs. Rat-Shank3 constructs were purified from an E.coli expression system and time-dependent protein aggregation was monitored using nuclear magnetic resonance (NMR). Our findings provide compelling evidence for the self-association of the SPN domain and suggest the potential to stabilize the domain, hindering this interaction and subsequent protein aggregation. These findings offer valuable insights into the molecular mechanisms underlying ASCs. Further investigations into the functional consequences of SPN-SPN interactions will enhance our understanding of the intermolecular mechanisms involved in ASCs.