Structural Models for the Dynamic Effects of Loss-of-Function Variants in the Human SIM1 Protein Transcriptional Activation Domain.
Structural Models for the Dynamic Effects of Loss-of-Function Variants in the Human SIM1 Protein Transcriptional Activation Domain.
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DOI：
10.3390/biom10091314
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发表时间：
2020-09-12
期刊：
影响因子：
5.5
通讯作者：
Caulfield TR
中科院分区：
文献类型：
--
作者：
Coban MA;Blackburn PR;Whitelaw ML;Haelst MMV;Atwal PS;Caulfield TR
SIM1是一种具有多种生理和发育功能的转录因子。SIM1是I类基本螺旋-环-螺旋- per - arnt - sim （bHLH-PAS）转录因子家族的成员，该家族还包括其他几个保守蛋白，包括缺氧诱导因子、芳烃受体、神经元PAS蛋白和CLOCK昼夜节律调节因子。最近对HIF-a-ARNT和CLOCK-BMAL1蛋白复合物的研究揭示了它们的bHLH、PASA和PASB结构域的组织，并提供了这些异二聚体蛋白复合物如何形成的见解；然而，SIM1的实验结构一直缺乏。在这里，我们描述了人类SIM1及其结合伙伴ARNT在异二聚物中的第一个全长原子结构模型，并利用最先进的模拟和算法分析了几种致病变异。使用局部和全局位置偏差度量，对单个突变体的结构基础的推断是根据可能改变蛋白质功能的有害结构重组来解决的。我们提出了新的实验来探索这些假设，并研究一个有趣的SIM1动态行为。构象动力学证明了局部和全局区域的构象变化，这代表了所提出的变体功能障碍的机制。此外，我们使用从头算混合模型进一步预测变异热点，这些热点可以用于测试反变异（恢复野生型函数）或基础研究探针。
Single-minded homologue 1 (SIM1) is a transcription factor with numerous different physiological and developmental functions. SIM1 is a member of the class I basic helix-loop-helix-PER-ARNT-SIM (bHLH–PAS) transcription factor family, that includes several other conserved proteins, including the hypoxia-inducible factors, aryl hydrocarbon receptor, neuronal PAS proteins, and the CLOCK circadian regulator. Recent studies of HIF-a-ARNT and CLOCK-BMAL1 protein complexes have revealed the organization of their bHLH, PASA, and PASB domains and provided insight into how these heterodimeric protein complexes form; however, experimental structures for SIM1 have been lacking. Here, we describe the first full-length atomic structural model for human SIM1 with its binding partner ARNT in a heterodimeric complex and analyze several pathogenic variants utilizing state-of-the-art simulations and algorithms. Using local and global positional deviation metrics, deductions to the structural basis for the individual mutants are addressed in terms of the deleterious structural reorganizations that could alter protein function. We propose new experiments to probe these hypotheses and examine an interesting SIM1 dynamic behavior. The conformational dynamics demonstrates conformational changes on local and global regions that represent a mechanism for dysfunction in variants presented. In addition, we used our ab initio hybrid model for further prediction of variant hotspots that can be engineered to test for counter variant (restoration of wild-type function) or basic research probe.
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