Harnessing functional variant analysis for the targeted design of inhibitors of UBE3A

UBE3A is an imprinted gene that encodes an E3 ubiquitin ligase (also known as UBE3A) associated with two developmental disorders. Deletion or loss-of-function mutations in maternal UBE3A cause Angelman syndrome, whereas duplication or gain-of-function mutations in maternal UBE3A are linked to mood disorders and a prevalent form of autism. Such genetic evidence implicates UBE3A as an important target for potential therapeutic development.

To date, inhibitors of UBE3A have not been identified. Jason Yi’s lab has recently developed new and efficient cell-based methods to assess the functional impact of missense variants in UBE3A¹. This work has allowed them to identify numerous ‘hyper-modulatory’ sites in UBE3A², which are amino acid positions that mediate the active and inactive states of the enzyme. In subsequent preliminary studies, they used a combination of structural analysis and functional assays to identify the substrate-binding domain (S-domain) in UBE3A. Moreover, pilot studies have demonstrated how peptides that bind the S-domain can globally inhibit UBE3A activity toward all substrates, thereby providing a method to develop UBE3A inhibitors.

In the current project, Yi and his team plan to build on these studies to further characterize the role of the S-domain in UBE3A function and to identify and optimize peptides that can inhibit UBE3A activity by using biophysical methods and a mouse model possessing a gain-of-function mutation in Ube3a^2. Findings from these studies are expected to provide a new class of rationally designed inhibitors that target UBE3A activity and provide a path forward to develop therapies for disorders caused by mutations in UBE3A.

References

1. Stelzer J.A. and Yi J.J. J. Vis. Exp. 188, 10.3791/64454 (2022) PubMed
2. Weston K.P. et al. Nat. Commun. 12, 6809 (2021) PubMed