An Autism-Linked Mutation Disables Phosphorylation Control of UBE3A

被引：132

作者：

Yi, Jason J. ^{[1
,2
,3
,4
]}

Berrios, Janet ^{[1
,2
]}

Newbern, Jason M. ^{[5
]}

Snider, William D. ^{[1
,2
,4
]}

Philpot, Benjamin D. ^{[1
,2
,4
]}

Hahn, Klaus M. ^{[3
]}

Zylka, Mark J. ^{[1
,2
,4
]}

机构：

[1] Univ N Carolina, Dept Cell Biol & Physiol, Chapel Hill, NC 27599 USA

[2] Univ N Carolina, UNC Neurosci Ctr, Chapel Hill, NC 27599 USA

[3] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA

[4] Univ N Carolina, Carolina Inst Dev Disabil, Chapel Hill, NC 27599 USA

[5] Arizona State Univ, Sch Life Sci, Tempe, AZ 85287 USA

来源：

CELL | 2015年 / 162卷 / 04期

基金：

美国国家卫生研究院;

关键词：

ANGELMAN SYNDROME GENE; UBIQUITIN LIGASE; UBE3A/E6-AP; EXPRESSION; DEFICITS; BINDING; MOUSE; P53;

D O I：

10.1016/j.cell.2015.06.045

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：795 / 807

页数：13

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