Unusual Rel-like architecture in the DNA-binding domain of the transcription factor NFATc
Unusual Rel-like architecture in the DNA-binding domain of the transcription factor NFATc
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DOI：
10.1038/385172a0
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发表时间：
1997-01-09
期刊：
影响因子：
64.8
通讯作者：
Verdine, GL
中科院分区：
文献类型：
--
作者：
Wolfe, SA;Zhou, P;Verdine, GL
NFAT家族的转录因子调节协调免疫反应的效应蛋白的产生(1)。免疫抑制药物FK506和环孢菌素A(CsA)通过阻断钙离子介导的导致NFAT的信号通路发挥作用。尽管FK506和CsA使人体器官能够常规地重新移植，但这些药物的毒副作用限制了它们的使用。这种毒性在直接针对NFAT的拮抗剂中可能是不存在的。作为基于结构寻找NFAT拮抗剂的第一步，我们现在报告了NFATc的一个20K结构域(NFATc-DBD)的鉴定和溶液结构，它是结合DNA和协同激活转录的必要条件和充分条件。虽然NFATc DNA阻碍结构域的总折叠与NF-kappa B p50的折叠有关(参考文献2，3)，但这两种蛋白质在DNA识别方面使用了显著不同的策略。在这些结果的基础上，我们提出了NFAT与IL-2增强子上的有丝分裂转录因子AP-1之间形成合作复合体的模型。
TRANSCRIPTION factors of the NFAT family regulate the production of effector proteins that coordinate the immune response(1). The immunosuppressive drugs FK506 and cyclosporin A (CsA) act by blocking a Ca2+-mediated signalling pathway leading to NFAT. Although FK506 and CsA have enabled human organs to Re transplanted routinely, the toxic side-effects of these drugs limit their usage. This toxicity might be absent in antagonists that target NFAT directly. As a first step in the structure-based search for NFAT antagonists, we now report the identification and solution structure of a 20K domain of NFATc (NFATc-DBD) that is both necessary and sufficient to bind DNA and activate transcription cooperatively. Although the overall fold of the NFATc DNA-hinding domain is related to that of NF-kappa B p50 (refs 2, 3), the two proteins use significantly different strategies for DNA recognition. On the basis of these results, we present a model for the cooperative complex formed between NFAT and the mitogenic transcription factor AP-1 on the interleukin-2 enhancer.