An Autism-Linked Mutation Disables Phosphorylation Control of UBE3A

Jason J YiMark J Zylka


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.


Jan 1, 1997·Nature Genetics·T KishinoJoseph Wagstaff
Sep 1, 1997·Nature Genetics·T H Vu, A R Hoffman
Jun 19, 1998·American Journal of Human Genetics·P MalzacJoseph Wagstaff
Aug 4, 1998·European Journal of Biochemistry·U NuberMartin Scheffner
Jun 22, 1999·The Journal of Biological Chemistry·S KumarPeter M Howley
Aug 17, 1999·International Journal of Cancer. Journal International Du Cancer·P PisaniJ Ferlay
Aug 19, 1999·The Journal of Pathology·J M WalboomersN Muñoz
Apr 13, 2004·Proceedings of the National Academy of Sciences of the United States of America·Andrew I SuJohn B Hogenesch
Jul 21, 2004·The Journal of Biological Chemistry·Eric M CooperPeter M Howley
Oct 9, 2008·Neurobiology of Disease·Amber HogartN Carolyn Schanen
May 12, 2009·Nature Neuroscience·Koji YashiroBenjamin D Philpot
Dec 17, 2009·The Journal of Biological Chemistry·Renuka K PandyaHidde L Ploegh
Mar 10, 2010·Proceedings of the National Academy of Sciences of the United States of America·Masaaki Sato, Michael P Stryker
May 20, 2011·Trends in Neurosciences·Angela M MabbBenjamin D Philpot
Jun 10, 2011·The Journal of Biological Chemistry·Yuan LuJohannes W Hell
Sep 29, 2011·Journal of Biomolecular NMR·Alexander LemakCheryl H Arrowsmith
Mar 16, 2013·Autism Research : Official Journal of the International Society for Autism Research·Nora UrracaLawrence T Reiter
Nov 26, 2013·The Journal of Biological Chemistry·Virginia P RonchiArthur L Haas
Apr 20, 2014·Molecular Biology of the Cell·Andrew D JacobsonChang-Wei Liu
Sep 13, 2014·Human Mutation·Bekim SadikovicPing Fang
Nov 5, 2014·Nature·Silvia De RubeisJoseph D Buxbaum
Nov 5, 2014·Nature·Ivan IossifovMichael Wigler
Nov 25, 2014·Nature Communications·Claire PiochonChristian Hansel
Jan 27, 2015·Annual Review of Pathology·Jason A ChenDaniel H Geschwind


Nov 13, 2015·Expert Opinion on Therapeutic Targets·Xiaoning BiMichel Baudry
Apr 17, 2016·Journal of the Neurological Sciences·N Thushara Vijayakumar, M V Judy
Oct 4, 2015·Nature·Ype Elgersma
May 18, 2016·Proceedings of the National Academy of Sciences of the United States of America·Menglong ZengMingjie Zhang
Aug 3, 2016·Chemical Science·David T KristAlexander V Statsyuk
Jun 25, 2016·The Journal of Comparative Neurology·Alain C BuretteRichard J Weinberg
Jul 2, 2016·Journal of Neurochemistry·Susana R Louros, Emily K Osterweil
Dec 1, 2017·Acta Biochimica Et Biophysica Sinica·Risa Kashima, Akiko Hata
Oct 11, 2017·Biological Chemistry·Sonja Lorenz
Sep 21, 2017·Nature Reviews. Molecular Cell Biology·Michael Rape
Aug 9, 2018·Chembiochem : a European Journal of Chemical Biology·Dan ChenSonja Lorenz
Jan 29, 2019·Human Molecular Genetics·Ryohei FurumaiToru Takumi
Mar 3, 2017·Current Protocols in Chemical Biology·David T KristAlexander V Statsyuk
Jan 11, 2017·The EMBO Journal·Ilan AttaliGali Prag
Jun 12, 2019·Translational Psychiatry·J C LauterbornJ N Crawley
Jan 25, 2020·Molecular Neurobiology·Maria A KashermanMichael Piper
Jan 30, 2020·Protein Science : a Publication of the Protein Society·Lena K RiesSonja Lorenz
Dec 24, 2019·Journal of Neuroscience Research·Xin Yang
Oct 27, 2018·Molecular Autism·Alain C BuretteRichard J Weinberg
Jul 14, 2017·Molecular Autism·Jamie ReillySanbing Shen
Feb 28, 2018·Dermato-endocrinology·Dianne E Godar, Stephen J Merrill
Dec 21, 2018·Frontiers in Molecular Neuroscience·Naman Vatsa, Nihar Ranjan Jana
Oct 27, 2018·Nature Communications·Carolin SailerFlorian Stengel
May 31, 2019·Molecular Autism·Monica SonzogniYpe Elgersma
Jul 28, 2020·Frontiers in Molecular Neuroscience·Shin-Ichi HisanagaMineko Tomomura
Jun 7, 2017·Acta Neuropathologica·Merina VarghesePatrick R Hof
Dec 2, 2016·Frontiers in Cellular Neuroscience·Yu-Chih LinGene J Blatt
May 19, 2017·Epigenetics & Chromatin·Paul R HillmanScott V Dindot
Jan 11, 2017·Journal of Biochemistry·Yasushi Saeki
Mar 16, 2017·Nature·Vaishnav KrishnanMatthew P Anderson
May 24, 2017·Bioscience Reports·Xie YingjunSun Xiaofang
Jan 29, 2019·Frontiers in Molecular Neuroscience·Simon Jesse LopezJanine M LaSalle
Oct 6, 2020·Frontiers in Cellular Neuroscience·Erin N Lottes, Daniel N Cox
Jun 3, 2018·Cellular and Molecular Life Sciences : CMLS·Jasper Sluimer, Ben Distel
Oct 19, 2019·Proceedings of the National Academy of Sciences of the United States of America·Luca ZammataroAlessandro D Santin
Sep 5, 2019·Frontiers in Cellular Neuroscience·Lauren Rylaarsdam, Alicia Guemez-Gamboa
Nov 6, 2020·Brain and Behavior·Peter A PerrinoRoslyn Holly Fitch
Aug 29, 2020·Neuroscience and Biobehavioral Reviews·Sehrish JavedWei-Hsiang Huang
Jul 30, 2019·Molecular and Cellular Neurosciences·Wen-Qi LiYun Wang

Related Concepts

UBE3A protein, human
Autistic Disorder
Embryonic Structures, Mammalian
Enzyme Stability
Mice, Inbred C57BL
Mutagenesis Process
Angelman Syndrome

Related Feeds

Cell eTOC

Cell is a scientific journal publishing research across a broad range of disciplines within the life sciences field. Discover the latest research from Cell here.


Autism spectrum disorder is associated with challenges with social skills, repetitive behaviors, and often accompanied by sensory sensitivities and medical issues. Here is the latest research.

Angelman Syndrome

Angelman syndrome is a neurogenetic imprinting disorder caused by loss of the maternally inherited UBE3A gene and is characterized by generalized epilepsy, limited expressive speech, sleep dysfunction, and movement disorders. Here is the latest research.

Related Papers

Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics
Seth S MargolisLynne M Bird
© 2021 Meta ULC. All rights reserved