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Three dimensional structures of SH2 and SH3 domains of the Abl and Shc oncoproteins.

机译：Abl和Shc癌蛋白的SH2和SH3域的三维结构。

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摘要

Src homology (SH) domains 2 and 3 are noncatalytic domains that are conserved among a series of cytoplasmic signaling proteins regulated by receptor protein kinases and nonreceptor kinases. SH2 and SH3 domains mediate protein-protein interactions by their ability to bind to specific phosphorylated tyrosine residues or proline-rich sequences, respectively. The SH2 and SH3 domains also have been shown to have regulatory functions for the catalytic domains of proteins which contain them. Binding of ligands to these domains can activate or inhibit the catalytic functions of the proteins.;Structure of the Abl SH3-SH2 domains has been determined at a resolution of 2.5 A with an R-factor of 18.3%. The structure shows that the protein exists as a monomer with significant intramolecular contact between the bc loop of the SH3 domain and BC loop of the SH2 domain. In addition, compared to other SH2 structures, the Abl SH3-SH2 structure shows that the BC loop of the SH2 domain is flatter, and the resulting phosphotyrosine pocket is narrow. These results suggest that there are direct interactions between the SH3 and SH2 domains, and that these interactions may affect the ligand binding properties of the SH2 domain. The results are also consistent with biochemical data which showed that the functions of one of the domains are influenced by the other.;Structures of the Abl SH2 domain, and complex of the SH2 domain and phosphotyrosine containing peptide were determined at a resolution of 3.0 A with R-factors of 18.7% and 19.2%, respectively. Overall structures of the liganded and unligated Abl SH2 domains are very close to that of the SH2 part in the Abl SH3-SH2 structure except in the BC loop. Mechanisms for the pTyr binding are similar to those shown in other SH2/peptide complex structures.;Crystal structure of the Shc SH2 domain has been determined at a resolution of 2.2A with an R-factor of 20.8%. Compared to the Abl SH2 domain, the Shc SH2 domain has a relatively longer BG loop, and the BG loop contains two short antiparallel ;Three dimensional structures of SH2 and SH3-SH2 domains of Abl tyrosine kinase, and SH2 domain of Shc protein have been determined by X-ray crystallography. Abl protein is one of a few proteins which are directly involved in human malignancies. Biochemical studies with Abl SH3-SH2 domains showed that relative positions of the two domains are important for their regulatory functions for the catalytic function of the Abl protein. The structure of the Shc SH2 domain which has unique ligand specificities was determined to investigate the structural basis for the specificities.
机译：Src同源（SH）域2和3是非催化域，在受受体蛋白激酶和非受体激酶调节的一系列细胞质信号蛋白中保守。 SH2和SH3域分别通过结合特定磷酸化酪氨酸残基或富含脯氨酸的序列的能力来介导蛋白质-蛋白质相互作用。还已经显示出SH2和SH3结构域对包含它们的蛋白质的催化结构域具有调节功能。配体与这些结构域的结合可以激活或抑制蛋白质的催化功能。已确定Abl SH3-SH2结构域的结构的分辨率为2.5 A，R因子为18.3％。结构表明该蛋白质以单体形式存在，在SH3结构域的bc环和SH2结构域的BC环之间具有明显的分子内接触。另外，与其他SH2结构相比，Abl SH3-SH2结构显示SH2结构域的BC环更平坦，并且所得的磷酸酪氨酸口袋狭窄。这些结果表明SH3和SH2域之间存在直接的相互作用，并且这些相互作用可能会影响SH2域的配体结合特性。结果也与生化数据一致，生化数据表明其中一个结构域的功能受到另一个结构域的影响。; Abl SH2结构域的结构以及SH2结构域与含磷酸酪氨酸肽的复合物的分辨率为3.0A。 R因子分别为18.7％和19.2％。除了在BC环中，配体和未连接的Abl SH2结构域的整体结构与Abl SH3-SH2结构中的SH2部分的整体结构非常接近。 pTyr结合的机制与其他SH2 /肽复合物结构中显示的机制相似。Shc SH2结构域的晶体结构已在2.2A的分辨率下确定，R因子为20.8％。与Abl SH2结构域相比，Shc SH2结构域具有相对较长的BG环，并且BG环包含两个短的反平行; Abl酪氨酸激酶的SH2和SH3-SH2结构域的三维结构以及Shc蛋白的SH2结构域已经被由X射线晶体学测定。 Abl蛋白是几种直接参与人类恶性肿瘤的蛋白之一。 Abl SH3-SH2域的生化研究表明，两个域的相对位置对其Abl蛋白催化功能的调控功能很重要。确定具有独特的配体特异性的Shc SH2结构域的结构，以研究特异性的结构基础。

著录项

  • 作者

    O, Hyun-Joo Nam.;

  • 作者单位

    Harvard University.;

  • 授予单位 Harvard University.;
  • 学科 Molecular biology.;Biochemistry.;Biophysics.
  • 学位 Ph.D.
  • 年度 1996
  • 页码 232 p.
  • 总页数 232
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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