Phosphorylation orchestrates the structural ensemble of the intrinsically disordered protein HMGA1a and modulates its DNA binding to the NF kappa B promoter

Kohl Bastian; Zhong Xueyin; Herrmann Christian; Stoll Raphael

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Phosphorylation orchestrates the structural ensemble of the intrinsically disordered protein HMGA1a and modulates its DNA binding to the NF kappa B promoter

机译：磷酸化核对本质上紊乱的蛋白质HMGA1a的结构集合，并调节其与NF kappa B启动子的DNA结合

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High Mobility Group Protein A1a (HMGA1a) is a highly abundant nuclear protein, which plays a crucial role during embryogenesis, cell differentiation, and neoplasia. Here, we present the first ever NMR-based structural ensemble of full length HMGA1a. Our results show that the protein is not completely random coil but adopts a compact structure consisting of transient long-range contacts, which is regulated by post-translational phosphorylation. The CK2-, cdc2- and cdc2/CK2-phosphorylated forms of HMGA1a each exhibit a different binding affinity towards the PRD2 element of the NF kappa B promoter. Our study identifies connected regions between phosphorylation sites in the wildtype ensemble that change considerably upon phosphorylation, indicating that these posttranslational modifications sites are part of an electrostatic contact network that alters the structural ensemble by shifting the conformational equilibrium. Moreover, ITC data reveal that the CK2-phosphorylated HMGA1a exhibits a different DNA promoter binding affinity for the PRD2 element. Furthermore, we present the first structural model for AT-hook 1 of HMGA1a that can adopt a transient alpha-helical structure, which might serve as an additional regulatory mechanism in HMAG1a. Our findings will help to develop new therapeutic strategies against HMGA1a-associated cancers by taking posttranslational modifications into consideration.

机译：高迁移率组蛋白A1A（HMGA1A）是一种高度丰富的核蛋白质，其在胚胎发生，细胞分化和肿瘤期间起着至关重要的作用。在这里，我们介绍了全长HMGA1A的第一个基于NMR的结构集合。我们的结果表明，蛋白质不是完全随机的线圈，但采用紧凑的结构，包括由翻译后磷酸化的瞬态远程触点组成。 CK2，CDC2和CDC2 / CK2-磷酸化形式的HMGA1A各自对NFκB启动子的PRD2元件表现出不同的结合亲和力。我们的研究识别野生型集合中的磷酸化位点之间的连接区域，该磷酸化在磷酸化时变化，表明这些后式修改位点是通过转移构象平衡而改变结构集合的静电接触网络的一部分。此外，ITC数据显示CK2-磷酸化的HMGA1A对PRD2元件表现出不同的DNA启动子结合亲和力。此外，我们介绍了HMGA1A的钩1的第一结构模型，其可以采用瞬态α-螺旋结构，其可以作为HMAG1A中的额外调节机制。我们的调查结果将有助于通过考虑出发后修改来帮助对HMGA1A相关癌症的新治疗策略。

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《Nucleic Acids Research》 |2019年第22期|共15页
作者
Kohl Bastian; Zhong Xueyin; Herrmann Christian; Stoll Raphael;
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Ruhr Univ Bochum Fac Chem &

Biochem Biomol NMR Spect Univ Str 150 D-44780 Bochum Germany;

Ruhr Univ Bochum Fac Chem &

Biochem Biomol NMR Spect Univ Str 150 D-44780 Bochum Germany;

Ruhr Univ Bochum Fac Chem &

Biochem Prot Interact Univ Str 150 D-44780 Bochum Germany;

Ruhr Univ Bochum Fac Chem &

Biochem Biomol NMR Spect Univ Str 150 D-44780 Bochum Germany;

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正文语种 eng
中图分类生物化学;
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专利

1. Phosphorylation orchestrates the structural ensemble of the intrinsically disordered protein HMGA1a and modulates its DNA binding to the NF kappa B promoter [J] . Kohl Bastian, Zhong Xueyin, Herrmann Christian, Nucleic Acids Research . 2019,第22期

机译：磷酸化核对本质上紊乱的蛋白质HMGA1a的结构集合，并调节其与NF kappa B启动子的DNA结合
2. C|[sol]|EBP|[alpha]| or C|[sol]|EBP|[alpha]| oncoproteins regulate the intrinsic and extrinsic apoptotic pathways by direct interaction with NF-|[kappa]|B p50 bound to the bcl-2 and FLIP gene promoters [J] . I Paz-Priel, A K Ghosal, J Kowalski, Leukemia . 2009,第2期

机译：C | [sol] | EBP |α|或C | [sol] | EBP |α|癌蛋白通过与与bcl-2和FLIP基因启动子结合的NF- |κ| B p50直接相互作用来调节内在和外在的凋亡途径
3. Function of NF-kappa B/Rel binding sites in the major histocompatibility complex class II invariant chain promoter is dependent on cell-specific binding of different NF-kappa B/Rel subunits. [J] . A M Brown, M W Linhoff, B Stein, Molecular and Cellular Biology . 1994,第5期

机译：在主要的组织相容性复合物II类不变链启动子中，NF-κB/ Rel结合位点的功能取决于不同NF-κB/ Rel亚基的细胞特异性结合。
4. Combining HDX-MS, Raman and SAXS Provides Structural Models of a Large Intrinsically Disordered Protein, which Folds upon Ligand Binding [C] . Darragh P. OBrien, Veronique Hourdel, Belen Hernandez, ASMS Conference on Mass Spectrometry and Allied Topics . 2015

机译：结合HDX-MS，拉曼和萨克斯提供了大型内在无序蛋白质的结构模型，其折叠在配体结合时
5. THE RESTRICTION ENDONUCLEASE ECO RI: ITS INTRINSIC METAL CENTER AND SPECIFIC INTERACTIONS WITH A DNA RECOGNITION SITE (PROTEIN-NUCLEIC ACID, ZINC METALLOENZYMES, INTERACTIONS CHIRAL METAL COMPLEXES, DNA-BINDING PROTEINS). [D] . PARANAWITHANA, SHANTHI R. 1986

机译：限制性内切酶Eco RI：其内在金属中心以及与DNA识别位点的特定相互作用（蛋白-核酸，锌金属酶，相互作用的手性金属络合物，DNA结合蛋白）。
6. Phosphorylation orchestrates the structural ensemble of the intrinsically disordered protein HMGA1a and modulates its DNA binding to the NFκB promoter [O] . Bastian Kohl, Xueyin Zhong, Christian Herrmann, 2019

机译：磷酸化可调节内在无序蛋白HMGA1a的结构整体并调节其与NFκB启动子的DNA结合
7. The rel-associated pp40 protein prevents DNA binding of Rel and NF-kappa B: relationship with I kappa B beta and regulation by phosphorylation. [O] . L D Kerr, J Inoue, N Davis, 1991

机译：相关的PP40蛋白可防止Rel和NF-Kappa B的DNA结合：与I Kappa Bβ和通过磷酸化的调节关系。

Phosphorylation orchestrates the structural ensemble of the intrinsically disordered protein HMGA1a and modulates its DNA binding to the NF kappa B promoter

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