title: An Autism-Linked Mutation Disables Phosphorylation Control of UBE3A.
abstract: 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.
authors.affiliation: Department of Cell Biology and Physiology and UNC Neuroscience Center, The University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pharmacology, The University of North Carolina, Chapel Hill, NC 27599, USA; Carolina Institute for Developmental Disabilities, The University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Yi
authors.affiliation: Department of Cell Biology and Physiology and UNC Neuroscience Center, The University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Berrios
authors.affiliation: School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Newbern
authors.affiliation: Department of Cell Biology and Physiology and UNC Neuroscience Center, The University of North Carolina, Chapel Hill, NC 27599, USA; Carolina Institute for Developmental Disabilities, The University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Snider
authors.affiliation: Department of Cell Biology and Physiology and UNC Neuroscience Center, The University of North Carolina, Chapel Hill, NC 27599, USA; Carolina Institute for Developmental Disabilities, The University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Philpot
authors.affiliation: Department of Pharmacology, The University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Klaus M
authors.initials: KM
authors.lastname: Hahn
authors.affiliation: Department of Cell Biology and Physiology and UNC Neuroscience Center, The University of North Carolina, Chapel Hill, NC 27599, USA; Carolina Institute for Developmental Disabilities, The University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: zylka@med.unc.edu.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Zylka
mesh_terms: D017204:Angelman Syndrome / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000473:pathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D049229:Dendritic Spines / Q000473:pathology; D004622:Embryo, Mammalian / Q000378:metabolism; D004795:Enzyme Stability; D005260:Female; D006801:Humans; D008810:Mice, Inbred C57BL; D016296:Mutagenesis; D020125:Mutation, Missense; D010766:Phosphorylation; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
chemical_list: C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases; D017868:Cyclic AMP-Dependent Protein Kinases