CRYSTAL-STRUCTURES OF PEPTIDE COMPLEXES OF THE AMINO-TERMINAL SH2 DOMAIN OF THE SYP TYROSINE PHOSPHATASE
CRYSTAL-STRUCTURES OF PEPTIDE COMPLEXES OF THE AMINO-TERMINAL SH2 DOMAIN OF THE SYP TYROSINE PHOSPHATASE
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DOI：
10.1016/s0969-2126(00)00044-7
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发表时间：
1994-05-15
期刊：
影响因子：
5.7
通讯作者：
KURIYAN, J
中科院分区：
文献类型：
--
作者：
LEE, CH;KOMINOS, D;KURIYAN, J
背景资料：Src同源2（SH 2）结构域以序列特异性方式结合磷酸酪氨酸残基，从而将酪氨酸磷酸化与信号转导分子的定位或催化活性的变化偶联。目前对SH 2特异性的理解是基于密切相关的Src和Lck酪氨酸激酶的SH 2-肽复合物的结构。酪氨酸磷酸酶Syp含有两个SH 2结构域，这两个结构域与酪氨酸激酶的结构域相对不同，具有不同的靶特异性，因此非常适合用于旨在扩展我们对SH 2特异性的理解的结构研究。Syp的氨基末端SH 2结构域与两种高亲和力肽的单独复合物的晶体结构，与非特异性肽复合的形式和未复合的形式已经在2埃和3埃之间的分辨率下被确定。SH 2结构域的结构和高亲和力肽结合的模式基本上类似于Src和Lck结构中所见。然而，结合界面是更广泛的Syp。结论：大多数SH 2目标具有疏水残基在第三位置后的磷酸酪氨酸，和Syp结构证实，该肽被锚定到SH 2表面由该残基和由磷酸酪氨酸。此外，Syp结构揭示了序列特异性可以延伸到磷酸酪氨酸之后的五个残基，并且显示了SH 2结构域的表面形貌如何随着特异性的变化而改变，同时保留了结构域的中心核心的结构。
Background: Src homology 2 (SH2) domains bind to phosphotyrosine residues in a sequence-specific manner, and thereby couple tyrosine phosphorylation to changes in the localization or catalytic activity of signal transducing molecules. Current understanding of SH2 specificity is based on the structures of SH2-peptide complexes of the closely-related Src and Lck tyrosine kinases. The tyrosine phosphatase Syp contains two SH2 domains that are relatively divergent from those of the tyrosine kinases, with distinct target specificities, and is thus well suited for structural studies aimed at extending our understanding of SH2 specificity.Results: Crystal structures of the amino-terminal SH2 domain of Syp in separate complexes with two high-affinity peptides, in complex with a non-specific peptide and in the uncomplexed form have been determined at between 2 angstrom and 3 angstrom resolution. The structure of the SH2 domain and the mode of high-affinity peptide binding is essentially similar to that seen in the Src and Lck structures. However, the binding interface is more extensive in Syp.Conclusions: Most SH2 targets have hydrophobic residues at the third position following the phosphotyrosine, and the Syp structure confirms that the peptide is anchored to the SH2 surface by this residue and by the phosphotyrosine. In addition, the Syp structure has revealed that sequence specificity can extend across the five residues following the phosphotyrosine, and has shown how the SH2 domain's surface topography can be altered with resulting changes in specificity, while conserving the structure of the central core of the domain.