Structures of HSF2 reveal mechanisms for differential regulation of human heat-shock factors.
Structures of HSF2 reveal mechanisms for differential regulation of human heat-shock factors.
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DOI：
10.1038/nsmb.3150
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发表时间：
2016-02
影响因子：
16.8
通讯作者：
Thiele DJ
中科院分区：
文献类型：
--
作者：
Jaeger AM;Pemble CW 4th;Sistonen L;Thiele DJ
热休克转录因子（HSF）家族成员在应激保护和人类疾病（包括蛋白质病、神经变性和癌症）中起作用。驱动特定HSF旁系同源物的不同翻译后修饰、辅因子募集和靶基因活化的机制尚不清楚。我们提出了与DNA结合的人类HSF2 DNA结合结构域（DBD）的高分辨率晶体结构，揭示了HSFs的前所未有的观点，为其独特的生物学提供了见解。HSF2 DBD结构解析了一种新的羧基末端螺旋，该螺旋引导卷曲螺旋结构域包裹DNA，暴露DBD表面的旁系同源特异性序列，用于差异翻译后修饰和辅因子相互作用。我们进一步证明了HSF1和HSF2之间通过其卷曲螺旋结构域的直接相互作用。总之，这些功能提供了一个新的模型HSF结构的基础上，差异和组合调节，影响转录反应细胞应激。
Heat Shock Transcription Factor (HSF) family members function in stress protection and in human disease including proteopathies, neurodegeneration and cancer. The mechanisms that drive distinct post-translational modifications, co-factor recruitment and target gene activation for specific HSF paralogs are unknown. We present high-resolution crystal structures of the human HSF2 DNA-binding domain (DBD) bound to DNA, revealing an unprecedented view of HSFs that provides insights into their unique biology. The HSF2 DBD structures resolve a novel carboxyl-terminal helix that directs the coiled-coil domain to wrap around DNA, exposing paralog-specific sequences of the DBD surface, for differential post-translational modifications and co-factor interactions. We further demonstrate a direct interaction between HSF1 and HSF2 through their coiled-coil domains. Together, these features provide a new model for HSF structure as the basis for differential and combinatorial regulation to influence the transcriptional response to cellular stress.