兒童神經(jīng)發(fā)育疾病“Rett綜合癥”是由MeCP2的突變引起的，后者是調(diào)控神經(jīng)元中的轉(zhuǎn)錄的一種蛋白。Michael Greenberg及其同事在MeCP2上發(fā)現(xiàn)了一個(gè)點(diǎn),，即threonine 308 (T308),，其磷酸化是由神經(jīng)活性調(diào)控的。T308磷酸化阻斷MeCP2與NCoR“共抑制因子復(fù)合物”的相互作用,，從而降低MeCP2抑制轉(zhuǎn)錄的能力,。攜帶MeCP2 T308突變的小鼠表現(xiàn)出與“Rett綜合癥”相關(guān)的癥狀，表明這種“依賴(lài)于活性的”磷酸化及MeCP2–NCoR相互作用的調(diào)控在“Rett綜合癥”中可能扮演著一個(gè)成因作用,。（生物谷Bioon.com）
生物谷推薦英文摘要：
Nature doi: 10.1038/nature12348
Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR
Daniel H. Ebert,Harrison W. Gabel,Nathaniel D. Robinson,Nathaniel R. Kastan, Linda S. Hu,Sonia Cohen,Adrija J. Navarro,Matthew J. Lyst,Robert Ekiert, Adrian P. Bird & Michael E. Greenberg
Rett syndrome (RTT) is an X-linked human neurodevelopmental disorder with features of autism and severe neurological dysfunction in females. RTT is caused by mutations in methyl-CpG-binding protein 2 (MeCP2), a nuclear protein that, in neurons, regulates transcription, is expressed at high levels similar to that of histones, and binds to methylated cytosines broadly across the genome. By phosphotryptic mapping, we identify three sites (S86, S274 and T308) of activity-dependent MeCP2 phosphorylation. Phosphorylation of these sites is differentially induced by neuronal activity, brain-derived neurotrophic factor, or agents that elevate the intracellular level of 3′,5′-cyclic AMP (cAMP), indicating that MeCP2 may function as an epigenetic regulator of gene expression that integrates diverse signals from the environment. Here we show that the phosphorylation of T308 blocks the interaction of the repressor domain of MeCP2 with the nuclear receptor co-repressor (NCoR) complex and suppresses the ability of MeCP2 to repress transcription. In knock-in mice bearing the common human RTT missense mutation R306C, neuronal activity fails to induce MeCP2 T308 phosphorylation, suggesting that the loss of T308 phosphorylation might contribute to RTT. Consistent with this possibility, the mutation of MeCP2 T308A in mice leads to a decrease in the induction of a subset of activity-regulated genes and to RTT-like symptoms. These findings indicate that the activity-dependent phosphorylation of MeCP2 at T308 regulates the interaction of MeCP2 with the NCoR complex, and that RTT in humans may be due, in part, to the loss of activity-dependent MeCP2 T308 phosphorylation and a disruption of the phosphorylation-regulated interaction of MeCP2 with the NCoR complex.
