Novel fold and wing structure of Forkhead transcription factor facilitate DNA binding.

IF 13.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
George L Wang,Yibei Jiang,Yuying Sun,Fariborz Nasertorabi,Jesse A Weller,Raktim Mitra,Alexander Batyuk,Oscar M Aparicio,Vadim Cherezov,Remo Rohs
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引用次数: 0

Abstract

Forkhead homologue 1 (Fkh1) is a yeast transcription factor that plays essential roles in cell-cycle dynamics. Here, we report the co-crystal structure of the DNA-binding domain (DBD) of the yeast Fkh1 protein in complex with a 19-base pair oligonucleotide containing the core binding site and flanking regions. The three-dimensional structure of the Fkh1-DBD reveals a previously unknown protein fold among all known Forkhead proteins. The winged-helix fold forms base-specific contacts of α-helix H3 with the major groove of the core binding site. Wing 1 and Wing 2 form DNA shape-mediated contacts with the minor groove of the binding site flanking regions. The conformation of Wing 2 is distinct from all known Forkhead proteins, with α-helices H5 and H6 wrapping back onto the protein core, creating a stable Wing 2 loop. Backbone interactions with β-strands S1 and S2 reveal a structural mechanism for previously observed flanking region preferences in SELEX-seq experiments. In vivo yeast experiments on Fkh1 mutants demonstrate that wing residues interacting with flanking regions are important for Fkh1 function. Molecular dynamics simulations relate Fkh1 function to conformational flexibility of wing residues. The novel Forkhead fold enables Fkh1 function with implications, such as structure-based protein design, for other DNA-binding proteins.
叉头转录因子新颖的折叠和翅膀结构促进DNA结合。
叉头同源物1 (Forkhead homologue 1, Fkh1)是酵母的一种转录因子,在细胞周期动力学中起重要作用。在这里,我们报道了酵母Fkh1蛋白的dna结合域(DBD)与包含核心结合位点和侧翼区域的19碱基对寡核苷酸复合物的共晶结构。Fkh1-DBD的三维结构揭示了所有已知叉头蛋白中先前未知的蛋白质折叠。翼状螺旋褶皱与核心结合位点主槽形成α-螺旋H3的碱基特异性接触。翼1和翼2与结合位点侧翼区域的小凹槽形成DNA形状介导的接触。Wing 2的构象与所有已知的Forkhead蛋白不同,α-螺旋H5和H6包裹回蛋白核心,形成稳定的Wing 2环。骨架与β-链S1和S2的相互作用揭示了SELEX-seq实验中先前观察到的侧翼区域偏好的结构机制。Fkh1突变体的体内酵母实验表明,与侧翼区域相互作用的翼残基对Fkh1的功能很重要。分子动力学模拟将Fkh1功能与机翼残基的构象柔韧性联系起来。新的叉头折叠使Fkh1功能具有启示意义,例如基于结构的蛋白质设计,用于其他dna结合蛋白。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Nucleic Acids Research
Nucleic Acids Research 生物-生化与分子生物学
CiteScore
27.10
自引率
4.70%
发文量
1057
审稿时长
2 months
期刊介绍: Nucleic Acids Research (NAR) is a scientific journal that publishes research on various aspects of nucleic acids and proteins involved in nucleic acid metabolism and interactions. It covers areas such as chemistry and synthetic biology, computational biology, gene regulation, chromatin and epigenetics, genome integrity, repair and replication, genomics, molecular biology, nucleic acid enzymes, RNA, and structural biology. The journal also includes a Survey and Summary section for brief reviews. Additionally, each year, the first issue is dedicated to biological databases, and an issue in July focuses on web-based software resources for the biological community. Nucleic Acids Research is indexed by several services including Abstracts on Hygiene and Communicable Diseases, Animal Breeding Abstracts, Agricultural Engineering Abstracts, Agbiotech News and Information, BIOSIS Previews, CAB Abstracts, and EMBASE.
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