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Molecular basis for regulation of CREB by cell stress and retroviral oncoproteins

细胞应激和逆转录病毒癌蛋白调节 CREB 的分子基础

基本信息

批准号：
10053716
负责人：
Ashok A Deniz
金额：
$ 59.92万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-05 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10053716
关键词：
Acute leukemia Address Binding Binding Proteins Biological Process Cardiovascular Diseases Cells Cellular Stress Color Communicable Diseases Complex Cyclic AMP Response Element Cyclic AMP-Responsive DNA-Binding Protein DNA DNA Binding Domain DNA Damage DNA-Binding Proteins Diabetes Mellitus Disease Distant E1A-associated p300 protein EP300 gene Event Genes Genetic Transcription Goals Hematopoiesis Hematopoietic Heteronuclear NMR Human Human T-Cell Leukemia Viruses Human T-lymphotropic virus 1 Knowledge Length Leucine Zippers Lymphoid Cell MYB gene Malignant Neoplasms Molecular Molecular Conformation Myeloid Leukemia Nature Neurodegenerative Disorders Oncogenic Oncoproteins Phosphorylation Physiological Play Post-Translational Protein Processing Post-Translational Regulation Protein Conformation Proteins Proteome Regulation Regulatory Pathway Research Roentgen Rays Role Signal Pathway Signal Transduction Site Stimulus Structure Techniques Viral Viral Proteins bZIP Domain biophysical tools cancer therapy cell transformation dimer flexibility genetic regulatory protein hematopoietic stem cell differentiation insight leukemia leukemia virus novel programs protein structure function response single molecule single-molecule FRET small molecule therapeutics structural biology therapeutic target transcription factor

项目摘要

Approximately one-third of the proteins in the human proteome are intrinsically disordered (IDPs). IDPs play a central role in cellular signaling and regulatory pathways and are directly implicated in numerous devastating diseases such as cancer, leukemia, diabetes, and neurodegenerative disease. Because of the central role of IDPs in signaling and regulation and the unique features of their complexes with their physiological partners, interactions involving disordered proteins are frequently targeted by viral proteins that mimic cellular IDP motifs. Many regulatory IDPs function through the transient assembly of multi- component signaling complexes, where flexibility and dynamic exchange of binding partners plays a critical role. The dynamic nature of IDPs and their regulatory complexes imposes a major challenge to traditional structural biology techniques. The overarching goal of this project is to characterize the conformational ensemble and interactions of a key intrinsically disordered transcription factor, the cyclic AMP response element binding protein (CREB), to elucidate the molecular mechanism by which its activity is down regulated by hyperphosphorylation in response to DNA damage and by binding to an important human T cell leukemia virus oncoprotein that promotes lymphoid cell transformation and progression of leukemia. CREB plays a critical role in regulating normal hematopoietic stem cell differentiation and is implicated in proliferation of myeloid and acute leukemias. Transcription of CREB- responsive genes is regulated by phosphorylation at multiple sites and by interactions with the CBP/p300 and CRTC coactivators. A powerful combination of complementary biophysical tools - NMR, single molecule FRET (smFRET), and small angle X-ray scattering (SAXS) – will be used to characterize the conformation of CREB and conformational changes associated with hyperphosphorylation and with binding to DNA, coactivators, and the basic leucine zipper oncoprotein (HBZ) of human T-cell leukemia virus type 1.

人类蛋白质组中大约三分之一的蛋白质是固有无序的(IDPs)。国内流离失所者在细胞信号和调节通路中发挥核心作用，并直接涉及到许多破坏性疾病，如癌症、白血病、糖尿病和神经退行性疾病。因为. 国内流离失所者在信号和调节中的核心作用及其与其复合体的独特特征生理伙伴，涉及无序蛋白质的相互作用经常是病毒蛋白质的目标模仿细胞内的IDP图案。许多受监管的IdP通过瞬时组装多个组件信令复合体，其中绑定伙伴的灵活性和动态交换起到了关键角色。国内流离失所者及其监管复合体的动态性质对以下方面构成重大挑战传统的结构生物学技术。这个项目的首要目标是描述一种关键的内在无序转录因子--环转录因子的构象集成和相互作用 AMP反应元件结合蛋白(CREB)，以阐明其分子机制反应DNA损伤的过度磷酸化和通过与一种重要的人类T细胞白血病病毒癌蛋白，促进淋巴细胞转化和白血病的进展。CREB在调节正常造血干细胞中起关键作用分化，并与髓系白血病和急性白血病的增殖有关。CREB-的转录应答基因受多个位点的磷酸化和与CBP/p300相互作用的调节和CRTC共激活剂。互补的生物物理工具的强大组合-核磁共振，单一分子FRET(SmFRET)和小角X射线散射(SAXS)-将用于表征 CREB的构象及其与过度磷酸化相关的构象变化与人类T细胞白血病的DNA、共激活剂和碱性亮氨酸拉链癌蛋白(HBZ)的结合病毒类型1。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Expanding the Paradigm: Intrinsically Disordered Proteins and Allosteric Regulation.

DOI：
10.1016/j.jmb.2018.04.003
发表时间：
2018-08-03
期刊：
Journal of molecular biology
影响因子：
5.6
作者：
Berlow RB;Dyson HJ;Wright PE
通讯作者：
Wright PE

NMR illuminates intrinsic disorder.

DOI：
10.1016/j.sbi.2021.03.015
发表时间：
2021-10
期刊：
Current opinion in structural biology
影响因子：
6.8
作者：
Dyson HJ;Wright PE
通讯作者：
Wright PE

Structural basis for cooperative regulation of KIX-mediated transcription pathways by the HTLV-1 HBZ activation domain.

HTLV-1 HBZ 激活域协同调节 KIX 介导的转录途径的结构基础。

DOI：
10.1073/pnas.1810397115
发表时间：
2018
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Yang,Ke;Stanfield,RobynL;Martinez-Yamout,MariaA;Dyson,HJane;Wilson,IanA;Wright,PeterE
通讯作者：
Wright,PeterE

Structural Basis for Graded Inhibition of CREB:DNA Interactions by Multisite Phosphorylation.

通过多位点磷酸化分级抑制 CREB:DNA 相互作用的结构基础。