An Autism-Linked Mutation Disables Phosphorylation Control of UBE3A

Jason J. Yi, Janet Berrios, Jason Newbern, William D. Snider, Benjamin D. Philpot, Klaus M. Hahn, Mark J. Zylka

Research output: Contribution to journalArticlepeer-review

109 Scopus citations


Summary Deletion of UBE3A causes the neurodevelopmental disorder Angelman syndrome (AS), while duplication or triplication of UBE3A is linked to autism. These genetic findings suggest that the ubiquitin ligase activity of UBE3A must be tightly maintained to promote normal brain development. Here, we found that protein kinase A (PKA) phosphorylates UBE3A in a region outside of the catalytic domain at residue T485 and inhibits UBE3A activity toward itself and other substrates. A de novo autism-linked missense mutation disrupts this phosphorylation site, causing enhanced UBE3A activity in vitro, enhanced substrate turnover in patient-derived cells, and excessive dendritic spine development in the brain. Our study identifies PKA as an upstream regulator of UBE3A activity and shows that an autism-linked mutation disrupts this phosphorylation control. Moreover, our findings implicate excessive UBE3A activity and the resulting synaptic dysfunction to autism pathogenesis.

Original languageEnglish (US)
Article number8292
Pages (from-to)795-807
Number of pages13
Issue number4
StatePublished - Aug 17 2015

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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