Structure and Function of the FOXP Family of Transcription Factors

FOXP 转录因子家族的结构和功能

• 批准号: 7215155
• 负责人: LIN CHEN
• 金额: $ 23.8万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7215155
• 关键词: Autoimmune Diseases; Binding; Binding Sites; Biochemical; Cell physiology; Cells; Collaborations; Complex; Cytokine Gene; DNA; DNA Binding; Diagnosis; Dimerization; Disease; Family; Gene Expression; Genetic; Goals; Health; Hereditary Disease; Homeostasis; Human; Immune Tolerance; Immune system; Interleukin-2; Investigation; Language Development; Lead; Length; Leucine Zippers; Link; Mediating; Methods; Modeling; Molecular; Molecular Target; Mus; Mutation; Numbers; Phenotype; Physiological; Play; Process; Protein Binding; Protein Family; Proteins; Research; Research Personnel; Role; Sequence Analysis; Signal Transduction; Site; Specificity; Speech Disorders; Structure; Syndrome; System; T-Lymphocyte; Transcription factor genes; Transcriptional Regulation; Tumor Suppression; X-Ray Crystallography; Zinc Fingers; base; cytokine; design; dimer; disease-causing mutation; human disease; immune function; in vivo; insight; interest; link protein; lung development; member; monomer; mouse model; mutant; novel strategies; programs; promoter; transcription factor; tumorigenesis

DESCRIPTION (provided by applicant): The long-term goal of the proposed research is to elucidate the molecular mechanisms by which FOXP transcription factors regulate specific gene expression in physiologically important processes. Mutations in FOXP proteins have been linked to human autoimmune disease (FOXP3) and speech disorder (FOXP2). Other members of the FOXP family have been implicated in tumor suppression (FOXP1) and lung development (FOXP4). Despite their significant physiological functions, the molecular mechanisms of this family of transcription factors are not well understood. FOXP contains a divergent forkhead domain and a number of distinct functional motifs, including a zinc finger/leucine zipper motif preceding the forkhead domain. There is also evidence that FOXP3 and NFAT1 physically interact and bind composite DNA sites cooperatively. Thus, either through intrinsic DNA binding or interaction with distinct partners, FOXP proteins possess unique DNA recognition mechanisms as compared classical FOX proteins, which in turn determine the transcriptional specificity of the FOXP family of transcription factors. The research proposed here will characterize the structure and function of FOXP proteins and their complexes with DNA and NFAT by X-ray crystallography and biochemical methods. Aim 1 will focus on the forkhead domains of FOXP proteins to characterize their detailed DNA recognition mechanisms. Aim 2 will analyze the structure of the zinc finger/leucine zipper motif and larger fragments or full-length FOXP proteins to see how other regions of FOXP modulate the function of this family of proteins. Aim 3 will study the structural basis of NFAT/FOXP interaction and its potential function in T cell gene expression. The detailed biochemical and structural studies proposed in this application will provide a molecular basis for analyzing the mechanisms of disease- associated mutations in FOXP proteins and further investigation of their normal physiological roles in diverse cellular processes. Health Relevance: Because mutations in FOXP proteins are linked to autoimmune disease and speech disorder, uncovering their unique DNA recognition mechanisms will help identify potential target genes of these transcription factors, which in turn can offer crucial insights into the mechanisms of human language development and immunological tolerance. These insights may lead to new approaches to diagnosing and treating human diseases incurred by malfunction of FOXP proteins.

描述（由申请人提供）：拟议研究的长期目标是阐明FOXP转录因子在生理上重要的过程中调节特定基因表达的分子机制。 FOXP蛋白的突变与人类自身免疫性疾病（FOXP3）和言语障碍（FOXP2）有关。 FOXP家族的其他成员也与肿瘤抑制（FOXP1）和肺发育（FOXP4）有关。尽管具有重要的生理功能，但该家族转录因子的分子机制尚未得到充分了解。 FOXP包含一个不同的叉子域和许多不同的功能基序，包括在叉子域之前的锌指/亮氨酸拉链图案。也有证据表明，FOXP3和NFAT1在物理上相互作用并结合复合DNA位点。因此，通过固有的DNA结合或与不同伴侣的相互作用，FOXP蛋白具有与经典FOX蛋白相比的独特DNA识别机制，这又决定了FoxP转录因子的转录特异性。这里提出的研究将通过X射线晶体学和生化方法来表征FOXP蛋白及其复合物与DNA和NFAT的结构和功能。 AIM 1将集中在FOXP蛋白的叉状结构域上，以表征其详细的DNA识别机制。 AIM 2将分析锌指/亮氨酸拉链基序的结构和较大的片段或全长FOXP蛋白，以查看FOXP的其他区域如何调节该蛋白质家族的功能。 AIM 3将研究NFAT/FOXP相互作用的结构基础及其在T细胞基因表达中的潜在功能。本应用中提出的详细生化和结构研究将为分析FOXP蛋白中疾病相关突变的机制提供分子基础，并进一步研究其在各种细胞过程中的正常生理作用。健康相关性：由于FOXP蛋白中的突变与自身免疫性疾病和言语障碍有关，因此发现其独特的DNA识别机制将有助于识别这些转录因子的潜在靶基因，这反过来又可以为人类语言发展机制提供重要的见解和免疫学耐受性。这些见解可能会导致诊断和治疗FOXP蛋白质功能障碍引起的人类疾病的新方法。