Structural and biological features of FOXP3 dimerization relevant to regulatory T cell function.
Structural and biological features of FOXP3 dimerization relevant to regulatory T cell function.
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DOI：
10.1016/j.celrep.2012.04.012
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发表时间：
2012-06-28
期刊：
影响因子：
8.8
通讯作者：
Greene MI
中科院分区：
文献类型：
--
作者：
Song X;Li B;Xiao Y;Chen C;Wang Q;Liu Y;Berezov A;Xu C;Gao Y;Li Z;Wu SL;Cai Z;Zhang H;Karger BL;Hancock WW;Wells AD;Zhou Z;Greene MI
Foxp3是调节T细胞功能的关键转录因子。我们报道了FOXP3盘绕结构域的晶体结构，通过它可以形成松散或瞬时的二聚体结合，并对其进行调制，从而解释了致病突变或翻译后修饰引起的活性变化。结构导向突变研究表明，FOXP3螺旋线圈介导的同源二聚化是体内和体外Treg功能所必需的。特别是，我们确定人FOXP3 K250和K252是FOXP3二聚体构象变化和稳定性的关键残基，这可以通过蛋白质翻译后修饰来调节，如可逆赖氨酸乙酰化。这些研究为在IPEX综合征中常见的FOXP3卷曲线圈结构域中的某些致病突变提供了结构和机制上的解释。总体上，涉及同源寡聚、乙酰化和异结合的调控机制已经被剖析，定义了对FOXP3复合体的生物学和病理特征的原子洞察。
FOXP3 is a key transcription factor for regulatory T cell function. We report the crystal structure of the FOXP3 coiled coil domain, through which a loose or transient dimeric association is formed and modulated, accounting for the activity variations introduced by disease-causing mutations or posttranslational modifications. Structure-guided mutagenesis revealed that FOXP3 coiled coil mediated homo-dimerization is essential for Treg function in vitro and in vivo. In particular, we identified human FOXP3 K250 and K252 as key residues for the conformational change and stability of the FOXP3 dimer, which can be regulated by protein posttranslational modifications such as reversible lysine acetylation. These studies provide structural and mechanistic explanations for certain disease-causing mutations in the coiled coil domain of FOXP3 that are commonly found in IPEX syndrome. Overall the regulatory machinery involving homo-oligomerization, acetylation, and hetero-association has been dissected, defining atomic insights into the biological and pathological characteristics of the FOXP3 complex.
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影响因子：
5
作者：
Mackey-Cushman, S. L.;Gao, J.;Holmes, D. A.;Nunoya, J-I;Wang, R.;Unutmaz, D.;Su, L.
通讯作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.0700298104
发表时间：
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影响因子：
11.1
作者：
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通讯作者：
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DOI：
10.1073/pnas.0509269102
发表时间：
2005-12-27
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Sakaguchi, Shimon