Allosteric Communication across STAT3 Domains Associated with STAT3 Function and Disease-Causing Mutation.
Allosteric Communication across STAT3 Domains Associated with STAT3 Function and Disease-Causing Mutation.
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DOI：
10.1016/j.jmb.2016.01.003
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发表时间：
2016-02-13
影响因子：
5.6
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Namanja AT;Wang J;Buettner R;Colson L;Chen Y
STAT 3是STAT转录激活因子的成员。由于组成性激活或突变引起的STAT 3活性的异常导致疾病，例如癌症和高免疫球蛋白E综合征（HIES）。STAT 3含有几个结构域，包括SH 2结构域、连接结构域（LD）、DNA结合结构域（DBD）和卷曲螺旋结构域（CCD）。在这里，我们报告了使用NMR和其他方法研究发现STAT 3中的结构域间变构通信。我们发现pTyr-肽与SH 2结构域的相互作用导致LD和DBD的结构和动力学变化。结构域间变构效应可能由疏水核心中的柔性介导。此外，在HIES中发现的LD突变（I568 F）诱导SH 2、DBD和CCD中的NMR化学位移扰动，表明这些结构域中的构象变化。与SH 2的构象变化一致，I568 F突变体降低了SH 2对含pTyr肽的结合亲和力。这项研究提供了动力学依赖性变构效应的一个例子，由于STAT家族蛋白质的结构保守性，在STAT 3中观察到的结构域间变构通信可能发生在其他STAT中。
STAT3 is a member of STAT transcription activators. Aberration in STAT3 activity due to constitutive activation or mutations leads to diseases such as cancer and hyper immunoglobulin E syndrome (HIES). STAT3 contains several structured domains including the SH2 domain, linker domain (LD), DNA-binding domain (DBD) and the coil-coil domain (CCD). Here we report the discovery of inter-domain allosteric communications in STAT3 from studies using NMR and other methods. We found that pTyr-peptide interactions with the SH2 domain cause structural and dynamic changes in LD and DBD. The inter-domain allosteric effect is likely mediated by the flexibility in the hydrophobic core. In addition, a mutation in LD found in HIES (I568F) induces NMR chemical shift perturbation in SH2, DBD and CCD, suggesting conformational changes in these domains. Consistent with conformational changes in SH2, the I568F mutant reduces SH2’s binding affinity to a pTyr-containing peptide. This study provides an example of dynamics-dependent allosteric effects, and due to the structural conservation of the STAT family of proteins, the inter-domain allosteric communication observed in STAT3 likely occurs in other STATs.