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固有无序控制着主转录因子 PU.1 的两种功能不同的二聚体。

Intrinsic disorder controls two functionally distinct dimers of the master transcription factor PU.1.

机构信息

Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA.

Advanced Science Research Center, City University of New York, New York, NY 10031, USA.

出版信息

Sci Adv. 2020 Feb 21;6(8):eaay3178. doi: 10.1126/sciadv.aay3178. eCollection 2020 Feb.

DOI:10.1126/sciadv.aay3178
PMID:32128405
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7034988/
Abstract

Transcription factors comprise a major reservoir of conformational disorder in the eukaryotic proteome. The hematopoietic master regulator PU.1 presents a well-defined model of the most common configuration of intrinsically disordered regions (IDRs) in transcription factors. We report that the structured DNA binding domain (DBD) of PU.1 regulates gene expression via antagonistic dimeric states that are reciprocally controlled by cognate DNA on the one hand and by its proximal anionic IDR on the other. The two conformers are mediated by distinct regions of the DBD without structured contributions from the tethered IDRs. Unlike DNA-bound complexes, the unbound dimer is markedly destabilized. Dimerization without DNA is promoted by progressive phosphomimetic substitutions of IDR residues that are phosphorylated in immune activation and stimulated by anionic crowding agents. These results suggest a previously unidentified, nonstructural role for charged IDRs in conformational control by mitigating electrostatic penalties that would mask the interactions of highly cationic DBDs.

摘要

转录因子是真核生物蛋白质组中构象无序的主要储库。造血主调控因子 PU.1 呈现出转录因子中最常见的无规卷曲区域 (IDR) 结构的明确模型。我们报告说，PU.1 的结构化 DNA 结合域 (DBD) 通过拮抗二聚体状态来调节基因表达，这种状态一方面受到同源 DNA 的控制，另一方面受到其近端带负电荷的 IDR 的控制。这两种构象由 DBD 的不同区域介导，而不需要连接的 IDR 的结构贡献。与 DNA 结合的复合物不同，未结合的二聚体明显不稳定。没有 DNA 的二聚化是通过 IDR 残基的逐步磷酸模拟取代来促进的，这些磷酸模拟取代在免疫激活中被磷酸化，并受到阴离子拥挤剂的刺激。这些结果表明，带电荷的 IDR 在构象控制中具有以前未被识别的非结构作用，通过减轻会掩盖高度阳离子 DBD 相互作用的静电惩罚。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/661c/7034988/85343f1adf95/aay3178-F6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/661c/7034988/651a5313cdad/aay3178-F1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/661c/7034988/e9ae894d9ce7/aay3178-F2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/661c/7034988/0873ebe12d42/aay3178-F3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/661c/7034988/dab876b3f7f9/aay3178-F4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/661c/7034988/fd7ca61a2216/aay3178-F5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/661c/7034988/85343f1adf95/aay3178-F6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/661c/7034988/651a5313cdad/aay3178-F1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/661c/7034988/e9ae894d9ce7/aay3178-F2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/661c/7034988/0873ebe12d42/aay3178-F3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/661c/7034988/dab876b3f7f9/aay3178-F4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/661c/7034988/fd7ca61a2216/aay3178-F5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/661c/7034988/85343f1adf95/aay3178-F6.jpg

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