Quaternary structure of p53: The light at the end of the tunnel
Quaternary structure of p53: The light at the end of the tunnel
复制标题
p53的四级结构：隧道尽头的光明
DOI：
10.1073/pnas.0705319104
复制
发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Z. Shakked
中科院分区：
文献类型：
--
作者：
Z. Shakked
真核转录因子属于一类蛋白质，其通常具有由内在无序片段连接的折叠结构域。这些模块化蛋白质具有抗结晶的固有问题，并且担心即使它们被结晶，由于晶体堆积效应，所得结构也可能不代表溶液中的结构。它们也很难通过NMR进行研究，因为它们通常很大。这类蛋白质的一个值得注意的成员是肿瘤抑制因子p53，它是细胞防御癌症的关键蛋白质（1-3）。p53是大约40%的固有无序的。在其四聚体结构的每条链的393个残基中，仅残基100-300（序列特异性结合DNA的核心结构域（CD））和残基324-355（四聚化结构域（泰特））折叠。通过X射线晶体学和NMR方法确定了这两个结构域的结构。CD采用免疫球蛋白样β三明治结构，为DNA结合表面提供支架（4，5）。泰特形成由两个紧密二聚体组成的对称四聚体，通过反平行β折叠和螺旋-螺旋相互作用稳定（6-9）。p53 DNA结合位点或应答元件的序列有四个亚位点，每个亚位点长5 bp，因此四聚体p53中的四个CD可以与一个应答元件结合。Okorokov等人（10）最近提出了一种基于冷冻电子显微镜和单颗粒分析的鼠p53结构模型。他们的模型是非常不寻常的，因为它是由一个歪斜的立方体与泰特被解离，使四个p53单体通过其N和C末端相互作用。CD在这种结构中的排列与DNA反应元件的四个亚位点的所有四个结合不相容，这表明了一种尚未被证明的替代结合模式。
Eukaryotic transcription factors belong to a class of proteins that often have folded domains linked by intrinsically disordered segments. These modular proteins have an inherent problem of being resistant to crystallization and the concern that even if they were crystallized the resultant structure might not be representative of the one in solution because of crystal packing effects. They are also difficult to study by NMR because they are generally so large. A notable member of this class of proteins is the tumor suppressor p53, which is the key protein in the cell's defenses against cancer (1–3). p53 is ≈40% intrinsically disordered. Of 393 residues of each chain of its tetrameric structure, only residues 100–300, the core domain (CD) that binds sequence specifically to DNA, and residues 324–355, the tetramerization domain (Tet), are folded. The structures of the two domains were determined by x-ray crystallography and NMR methods. The CD adopts an Ig-like β-sandwich that provides a scaffold for a DNA binding surface (4, 5). The Tet forms a symmetrical tetramer made of two tight dimers stabilized by an antiparallel β-sheet and helix–helix interactions (6–9). The sequences of the p53 DNA binding sites or response ele-ments have four subsites, 5 bp long each, so that four CDs in tetrameric p53 can bind to one response element. Okorokov et al. (10) recently proposed a model for the structure of murine p53 on the basis of cryoelectron microscopy and single-particle analysis. Their model was very unusual in that it is composed of a skewed cube with the Tet being dissociated, so that four p53 monomers interact via their N and C termini. The arrangement of the CDs in this structure is not compatible with all four binding to the four subsites of the DNA response element, suggesting an alternative binding mode that has yet to be proven.
DOI：
10.1073/pnas.96.5.1875
发表时间：
1999-03-02
影响因子：
11.1
作者：
Nagaich, AK;Zhurkin, VB;Harrington, RE
通讯作者：
Harrington, RE