Molecular details of Itk activation by prolyl isomerization and phospholigand binding: the NMR structure of the Itk SH2 domain bound to a phosphopeptide.
Molecular details of Itk activation by prolyl isomerization and phospholigand binding: the NMR structure of the Itk SH2 domain bound to a phosphopeptide.
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通过脯氨酰异构化和磷酸配体结合激活 Itk 的分子细节：与磷酸肽结合的 Itk SH2 结构域的 NMR 结构。
DOI：
10.1016/j.jmb.2005.12.073
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发表时间：
2006
影响因子：
5.6
通讯作者：
Andreotti,AmyH
中科院分区：
文献类型：
--
作者：
Pletneva,EkaterinaV;Sundd,Monica;Fulton,DBruce;Andreotti,AmyH
白细胞介素-2酪氨酸激酶（Itk）的Src同源2（SH 2）结构域是控制这种免疫学上重要的酶的活性的调节装置的关键组分。为了深入了解与Itk活化形式相关的结构特征，我们已经解决了与含磷酸酪氨酸的肽（pY）结合的SH 2结构域的NMR结构，并分析了由pY结合引起的反式氢键标量偶联（3 hJNC ′）的变化。一个单一的脯氨酰亚胺键在这个域的异构化是负责同时存在两个不同的SH 2构象。脯氨酰异构化指导配体识别：反式构象优先结合pY。SH 2/pY复合物的结构提供了对配体特异性的深入了解;无配体的反式SH 2构象异构体中的BG环被预先安排用于与配体的pY+3残基的最佳接触。对由氢键产生的3 hJNC '偶联的分析表明，结构变化从pY结合口袋传播到含有构象不均匀脯氨酸的CD环以及结构域相反位点上的αB螺旋。这些发现提供了一个结构框架，了解脯氨酰异构化和pY结合的Itk调节中的作用。
The Src homology 2 (SH2) domain of interleukin-2 tyrosine kinase (Itk) is a critical component of the regulatory apparatus controlling the activity of this immunologically important enzyme. To gain insight into the structural features associated with the activated form of Itk, we have solved the NMR structure of the SH2 domain bound to a phosphotyrosine-containing peptide (pY) and analyzed changes in trans-hydrogen bond scalar couplings (3hJNC′) that result from pY binding. Isomerization of a single prolyl imide bond in this domain is responsible for simultaneous existence of two distinct SH2 conformers. Prolyl isomerization directs ligand recognition: the trans conformer preferentially binds pY. The structure of the SH2/pY complex provides insight into the ligand specificity; the BG loop in the ligand-free trans SH2 conformer is pre-arranged for optimal contacts with the pY+3 residue of the ligand. Analysis of3hJNC′couplings arising from hydrogen bonds has revealed propagation of structural changes from the pY binding pocket to the CD loop containing conformationally heterogeneous proline as well as to the αB helix, on the opposite site of the domain. These findings offer a structural framework for understanding the roles of prolyl isomerization and pY binding in Itk regulation.