The molecular basis of FHA Domain:Phosphopeptide binding specificity and implications for phospho-dependent signaling mechanisms
The molecular basis of FHA Domain:Phosphopeptide binding specificity and implications for phospho-dependent signaling mechanisms
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DOI：
10.1016/s1097-2765(00)00114-3
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发表时间：
2000-11-01
期刊：
影响因子：
16
通讯作者：
Yaffe, MB
中科院分区：
文献类型：
--
作者：
Durocher, D;Taylor, IA;Yaffe, MB
叉头相关（FHA）结构域是一类普遍存在的信号传导模块，其似乎通过与磷酸化靶分子的相互作用而发挥功能。我们已经使用定向肽库筛选来确定由几个FHA结构域识别的最佳磷酸肽结合基序，包括许多DNA损伤检查点激酶内的那些，并确定了Rad 53 p-FHA 1与磷酸-苏氨酸肽复合的X射线结构，分辨率为1.6埃。结构揭示了一个惊人的相似性MH 2结构域的Smad肿瘤抑制蛋白，并揭示了一种模式的肽结合，不同于SH 2，14-3-3，或PTB结构域复合物。这些结果对DNA损伤信号传导和CHK 2依赖的肿瘤抑制具有重要意义，并且它们表明FHA结构域在原核生物和真核生物中的S/T激酶信号传导机制中发挥重要且未被怀疑的作用。
Forkhead-associated (FHA) domains are a class of ubiquitous signaling modules that appear to function through interactions with phosphorylated target molecules. We have used oriented peptide library screening to determine the optimal phosphopeptide binding motifs recognized by several FHA domains, including those within a number of DNA damage checkpoint kinases, and determined the X-ray structure of Rad53p-FHA1, in complex with a phospho-threonine peptide, at 1.6 Angstrom resolution. The structure reveals a striking similarity to the MH2 domains of Smad tumor suppressor proteins and reveals a mode of peptide binding that differs from SH2, 14-3-3, or PTB domain complexes. These results have important implications for DNA damage signaling and CHK2-dependent tumor suppression, and they indicate that FHA domains play important and unsuspected roles in S/T kinase signaling mechanisms in prokaryotes and eukaryotes.