The autoimmune regulator protein has transcriptional transactivating properties and interacts with the common coactivator CREB-binding protein
The autoimmune regulator protein has transcriptional transactivating properties and interacts with the common coactivator CREB-binding protein
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DOI：
10.1074/jbc.m908944199
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发表时间：
2000-06-02
影响因子：
4.8
通讯作者：
Peterson, P
中科院分区：
文献类型：
--
作者：
Pitkänen, J;Doucas, V;Peterson, P
自身免疫性多内分泌病念珠菌外胚层营养不良，由自身免疫调节基因（AIRE）突变引起，是一种常染色体隐性自身免疫性疾病，其特征是对器官特异性抗原的耐受性破坏。AIRE编码的545个氨基酸的蛋白含有几个提示转录调节因子的结构基序，并且与参与转录控制的细胞蛋白相似。我在这里展示了AIRE与异源DNA结合域的融合激活了来自报告子启动子的转录，并且所见的激活需要全长蛋白或多个激活域。在结构水平上，AIRE通过nh2末端结构域形成同型二聚体，该结构域的分子模型显示为四螺旋束结构。与此一致的是，我们发现共同的转录辅激活因子creb结合蛋白（CBP）在体外和酵母核中通过CH1和CH3保守结构域与AIRE相互作用。我们认为AIRE的转录转激活特性及其与CBP的相互作用可能对其功能很重要，因为致病突变几乎完全消除了激活作用。
Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy, caused by mutations in the autoimmune regulator (AIRE) gene, is an autosomal recessive autoimmune disease characterized by the breakdown of tolerance to organ-specific antigens. The 545 amino acid protein encoded by AIRE contains several structural motifs suggestive of a transcriptional regulator and bears similarity to cellular proteins involved in transcriptional control. me show here that AIRE fused to a heterologous DNA binding domain activates transcription from a reporter promoter, and the activation seen requires the full-length protein or more than one activation domain. At the structural level AIRE forms homodimers through the NH2-terminal domain, and molecular modeling for this domain suggests a four-helix bundle structure. In agreement, we show that the common transcriptional coactivator CREB-binding protein (CBP) interacts with AIRE in vitro and in yeast nuclei through the CH1 and CH3 conserved domains. We suggest that the transcriptional transactivation properties of AIRE together with its interaction with CBP might be important in its function as disease-causing mutations almost totally abolish the activation effect.