- Awarded: 2016
- Award Type: Explorer
- Award #: 442659
Many of the mutations known to be associated with autism spectrum disorder (ASD) affect protein complexes that support the development and function of synapses. SHANK3 encodes a postsynaptic scaffolding protein that is essential for synaptic communication, and disruptions in the SHANK3 gene have been implicated in ASD. In particular, mutations of the SHANK3 gene or deletion of the terminal end of chromosome 22 (i.e., 22q13.3) encompassing SHANK3 have been shown to lead to Phelan-McDermid syndrome (PMS), in which individuals display symptoms of ASD. The 22q13.3 region also encompasses genes encoding protein kinases and histone deacetylases. This raises the possibility that post-translational modifications of SHANK3 may function in the regulation of its gene expression patterns, and may also influence behavioral phenotypes seen in PMS.
Je-Hyun Yoon and his colleagues at the Medical University of South Carolina are characterizing how post-translational modifications affect SHANK3 biology. Preliminary data from Yoon’s team have demonstrated that RNF31, a ubiquitin E3 ligase that works in a complex with SHARPIN (SHANK-associated RH domain interacting protein), ubiquitinates SHANK3. The team has also identified a protein kinase as a binding partner for RNF31, and demonstrated that this kinase phosphorylates a key serine site on RNF31 known to critically regulate RNF31 ubiquitin enzymatic activity.
The current study aims to elucidate how RNF31 phosphorylation affects its ability to regulate ubiquitin-mediated degradation of SHANK3 . Yoon’s team will use mouse cortical neurons deficient in the identified protein kinase to examine SHANK3 ubiquitination and subsequent phosphorylation-dependent degradation by RNF31. This study will provide insight into fundamental mechanisms underlying how SHANK3 protein abundance is regulated by ubiquitin-mediated proteolysis, and how such modulation might affect the pathobiology seen in individuals with ASD-related disorders such as PMS.