Unique physical properties and interactions of the domains of methylated DNA binding protein 2.
Unique physical properties and interactions of the domains of methylated DNA binding protein 2.
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DOI：
10.1021/bi9019753
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发表时间：
2010-05-25
期刊：
影响因子：
2.9
通讯作者：
Woodcock, Christopher L.
中科院分区：
文献类型：
--
作者：
Ghosh, Rajarshi P.;Nikitina, Tatiana;Horowitz-Scherer, Rachel A.;Gierasch, Lila M.;Uversky, Vladimir N.;Hite, Kristopher;Hansen, Jeffrey C.;Woodcock, Christopher L.
MeCP 2是一种甲基CpG结合蛋白，其关键作用是识别DNA甲基化模式中编码的表观遗传信息。MeCP 2功能的突变或失调会导致Rett综合征以及各种其他自闭症谱系障碍。在这里，我们详细分析了六个单独表达的人类MeCP 2结构域跨越整个蛋白质的特性，重点是它们之间的相互作用，与DNA，和与核小体阵列。每个结构域对全长蛋白质的结构和功能都有独特的贡献。MeCP 2约60%为非结构化，具有9个散布的α-分子识别特征（α-MoRF），这些特征是预测在与结合伴侣形成复合物后获得二级结构的多肽片段。在一些分离的MeCP 2结构域和全长蛋白质中通过与DNA结合诱导二级结构含量的大幅增加。在我们的测定中观察到的一些MeCP 2结构域之间的顺式和反式相互作用可能有助于完整蛋白质的结构和功能。我们还表明，MeCP 2有两个功能的一半。N-末端部分含有甲基化的DNA结合结构域（MBD）和两个高度无序的侧翼结构域，其调节MBD介导的DNA结合。这些侧翼结构域之一也能够自主DNA结合。相比之下，蛋白质的C-末端部分含有至少两个独立的DNA结合结构域和染色质特异性结合结构域，主要负责介导核小体阵列压实和寡聚化。这些发现导致新的机制和生化的见解，这种内在的无序蛋白质的构象调制，其上下文依赖的体内作用。
MeCP2 is a methyl CpG binding protein whose key role is the recognition of epigenetic information encoded in DNA methylation patterns. Mutation or mis-regulation of MeCP2 function leads to Rett syndrome as well as a variety of other Autism Spectrum Disorders. Here, we have analyzed in detail the properties of six individually expressed human MeCP2 domains spanning the entire protein with emphasis on their interactions with each other, with DNA, and with nucleosomal arrays. Each domain contributes uniquely to the structure and function of the full-length protein. MeCP2 is ~60% unstructured, with nine interspersed α-Molecular Recognition Features (α-MoRFs), which are polypeptide segments predicted to acquire secondary structure upon forming complexes with binding partners. Large increases in secondary structure content are induced in some of the isolated MeCP2 domains and in the full-length protein by binding to DNA. Interactions between some MeCP2 domains in cis and trans seen in our assays, likely contribute to the structure and function of the intact protein. We also show that MeCP2 has two functional halves. The N-terminal portion contains the methylated DNA binding domain (MBD) and two highly disordered flanking domains which modulate MBD-mediated DNA binding. One of these flanking domains is also capable of autonomous DNA binding. In contrast, the C-terminal portion of the protein which harbors at least two independent DNA binding domains and a chromatin specific binding domain is largely responsible for mediating nucleosomal array compaction and oligomerization. These findings lead to new mechanistic and biochemical insights regarding the conformational modulations of this intrinsically disordered protein, and its context-dependent in vivo roles.
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影响因子：
6.8
作者：
Dunker, A. Keith;Silman, Israel;Sussman, Joel L.
通讯作者：
Sussman, Joel L.
DOI：
10.1046/j.1432-1033.2003.03714.x
发表时间：
2003-08-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Heitmann, B;Maurer, T;Brunner, E
通讯作者：
Brunner, E
影响因子：
4.8
作者：
Carro, S;Bergo, A;Landsberger, N
通讯作者：
Landsberger, N
影响因子：
4.8
作者：
Georgel, PT;Horowitz-Scherer, RA;Hansen, JC
通讯作者：
Hansen, JC
影响因子：
2.9
作者：
Chandler, SP;Guschin, D;Wolffe, AP
通讯作者：
Wolffe, AP