确定控制胰岛素基因活性的 MAFA 和 MAFB 转录因子的独特结构特征。

IF 4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of Biological Chemistry Pub Date : 2024-10-28 DOI:10.1016/j.jbc.2024.107938
Jeeyeon Cha, Xin Tong, Katie C Coate, Min Guo, Jin-Hua Liu, Garrett Reynolds, Emily M Walker, Richard A Stein, Hassane Mchaourab, Roland Stein
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引用次数: 0

摘要

MAFA和MAFB是相关的含碱性亮氨酸-拉链结构域的转录因子,它们在多种细胞环境(包括胰岛细胞的激素分泌)中具有重要的重叠和不同的调控作用。在这里,我们首先研究了通过 X 射线晶体结构分析获得的保守 MAF 蛋白-DNA 接触位点的突变如何影响其 DNA 结合和胰岛素增强子驱动活性。虽然这些相互作用大多是必不可少的,破坏它们会严重影响活性,但我们发现这些接触位点以外的区域也有助于转录活性。我们使用基于人工智能的结构预测程序 AlphaFold 2 来确定 MAFA 和 MAFB 的非 DNA 结合/二聚化序列的三维组织是否也存在差异。这项分析是针对野生型(WT)蛋白质以及致病的 MAFASer64Phe 和 MAFBSer70Alatrans 激活结构域突变体进行的,结果发现 MAFAWT 和 MAFBWT 之间以及 MAFASer64Phe 和 MAFAWT 之间存在差异,但 MAFBSer70Ala 和 MAFBWT 之间没有差异。此外,还观察到这些蛋白在其他富含小岛的转录因子存在时协同刺激胰岛素增强子驱动活性的能力存在差异。对 MAFA 和 MAFB 嵌合体的分析表明,这些特性受到 AlphaFold 2 预测的独特 C 端区域结构差异的影响。我们的研究结果揭示了这些密切相关蛋白的关键结构特征,这些特征影响了它们调控基因表达的能力。
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Defining unique structural features in the MAFA and MAFB transcription factors that control Insulin gene activity.

MAFA and MAFB are related basic-leucine-zipper domain-containing transcription factors which have important overlapping and distinct regulatory roles in a variety of cellular contexts, including hormone production in pancreatic islet cells. Here we first examined how mutating conserved MAF protein-DNA contact sites obtained from X-ray crystal structure analysis impacted their DNA-binding and Insulin enhancer-driven activity. While most of these interactions were essential and their disruption severely compromised activity, we identified that regions outside of these contact sites also contributed to transcriptional activity. AlphaFold 2, an artificial intelligence-based structural prediction program, was used to determine if there were also differences in the three-dimensional organization of the non-DNA binding/dimerization sequences of MAFA and MAFB. This analysis was conducted on the wildtype (WT) proteins as well as the pathogenic MAFASer64Phe and MAFBSer70Alatrans-activation domain mutants, with differences revealed between MAFAWT and MAFBWT as well as between MAFASer64Phe and MAFAWT, but not between MAFBSer70Ala and MAFBWT. Moreover, dissimilarities between these proteins were also observed in their ability to cooperatively stimulate Insulin enhancer-driven activity in the presence of other islet-enriched transcription factors. Analysis of MAFA and MAFB chimeras disclosed that these properties were influenced by their unique C-terminal region structural differences predicted by AlphaFold 2. Our findings have revealed key structural features of these closely related proteins that impact their ability to regulate gene expression.

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来源期刊
Journal of Biological Chemistry
Journal of Biological Chemistry Biochemistry, Genetics and Molecular Biology-Biochemistry
自引率
4.20%
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期刊介绍: The Journal of Biological Chemistry welcomes high-quality science that seeks to elucidate the molecular and cellular basis of biological processes. Papers published in JBC can therefore fall under the umbrellas of not only biological chemistry, chemical biology, or biochemistry, but also allied disciplines such as biophysics, systems biology, RNA biology, immunology, microbiology, neurobiology, epigenetics, computational biology, ’omics, and many more. The outcome of our focus on papers that contribute novel and important mechanistic insights, rather than on a particular topic area, is that JBC is truly a melting pot for scientists across disciplines. In addition, JBC welcomes papers that describe methods that will help scientists push their biochemical inquiries forward and resources that will be of use to the research community.
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