Structural and functional studies of the IkappaB kinase (IKK) complex

IkappaB 激酶 (IKK) 复合物的结构和功能研究

• 批准号: 8082641
• 负责人: Hao Wu
• 金额: $ 37.27万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-25 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8082641
• 关键词: Attention; Baculoviruses; Binding; Biochemical; Biological; C-terminal; Calorimetry; Cell Nucleus; Cells; Complex; Crystallization; Data; Disease; Electron Microscopy; Enzyme Kinetics; Family; Genetic Transcription; HTATIP2 gene; Heart; Helix-Loop-Helix Motifs; Hereditary Disease; Human; Human Herpesvirus 8; IkappaB kinase; Immune response; Inflammatory; Inflammatory Response; Insecta; Interleukin-1 Receptors; Length; Leucine Zippers; Ligation; Link; Malignant Neoplasms; Mediating; Molecular; Molecular Conformation; Mutation; N-terminal; Nuclear; Oncogene Proteins; Paper; Pathway interactions; Phosphorylation; Phosphotransferases; Polyubiquitin; Polyubiquitination; Proteins; Publishing; Receptors, Antigen, B-Cell; Reporting; Series; Signal Transduction; Structure; Surface Plasmon Resonance; System; T-Cell Receptor; Titrations; Toll-like receptors; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Ubiquitin; Virus Diseases; Zinc Fingers; base; cytokine; design; dimer; genetic regulatory protein; human disease; image reconstruction; inhibitor/antagonist; kinase inhibitor; light scattering; member; microbial; molecular mass; multicatalytic endopeptidase complex; mutant; protein protein interaction; public health relevance; receptor; response; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Transcription factors in the nuclear factor ?B (NF-?B) family are evolutionarily conserved master regulators of immune and inflammatory responses. They are activated in response to ligation of many receptors including T-cell receptors, B-cell receptors, members of the tumor necrosis factor (TNF) receptor superfamily and the Toll-like receptor/interleukin-1 receptor (TLR/IL-1R) superfamily. The I?B kinase (IKK), comprising IKKa and IKK¿, is at the heart of NF-?B activation and mediates two NF-?B activation pathways. The canonical NF-?B pathway is triggered by microbial and viral infections and pro-inflammatory cytokines and is dependent on IKK¿ phosphorylation and activation. The alternative pathway is triggered by certain members of the TNF cytokine family and selectively activates IKKa. Activated IKK phosphorylates I?Bs, leading to their polyubiquitination and subsequent degradation by the proteasome. The freed NF-?B dimers translocate to the nucleus to mediate transcription. Because of its importance in NF-?B activation, IKK, especially IKK¿, has become a potential therapeutic target for many human diseases. The regulatory protein NEMO (also known as IKK? or FIP-3) interacts with IKKa and/or IKK¿ to form the IKKa, IKK¿ or IKKa/¿ holo-complex. The intact IKK¿ holo-complex is approximately 700-900kD in molecular mass containing multiple copies of IKK2 and NEMO. IKKa and IKK¿ both contain the following conserved recognizable domains: a kinase domain (KD), a leucine zipper domain (LZ), a helix loop helix domain (HLH) and a C-terminal NEMO-binding domain (NBD). NEMO contains an N-terminal kinase-binding domain (KBD), a minimal oligomerization domain (MOD) that is also the ubiquitin binding domain (UBD) and a C-terminal zinc finger domain (ZF). IKK and NF-?B signaling has attracted tremendous attention with more than 30,000 papers published on the subject. Despite the biological importance, not a single successful structure determination has been reported on IKK, an indication on the difficulty of the project. To elucidate the molecular basis of IKK function and to assist the discovery of IKK inhibitors, we propose a series of structural and functional studies on IKK, in particular, IKK¿ and its regulatory protein NEMO. Public Health Relevance: The I?B kinase (IKK) is at the heart of NF-?B activation and a potential therapeutic target for many human diseases. The proposal seeks structural studies of IKK, which will enhance our understanding on the molecular basis of IKK function. In addition, the proposed studies will provide a structural basis for discovery and optimization of IKK inhibitors in the treatment of inflammatory diseases and cancer.

描述（申请人提供）：核因子中的转录因子？B（NF-？B）家族是进化上保守的免疫和炎症反应的主调节因子。它们响应于许多受体的连接而被激活，所述受体包括T细胞受体、B细胞受体、肿瘤坏死因子（TNF）受体超家族和Toll样受体/白细胞介素-1受体（TLR/IL-1 R）超家族的成员。我？B激酶（IKK），包括IKKa和IKK，是NF-？B激活，并介导两个NF-？B激活途径。典型的NF-？B通路由微生物和病毒感染以及促炎细胞因子触发，并且依赖于IKK磷酸化和活化。旁路途径由TNF细胞因子家族的某些成员触发并选择性激活IKKa。激活IKK磷酸化I？Bs，导致它们的多聚泛素化和随后的蛋白酶体降解。被释放的NF-？B二聚体易位到细胞核中以介导转录。因为它在NF-？B活化，IKK，特别是IKK，已成为许多人类疾病的潜在治疗靶点。调节蛋白NEMO（也称为IKK？或FIP-3）与IKKa和/或IKK <$相互作用以形成IKKa、IKK <$或IKKa/<$全复合物。完整的IKK全复合物分子量约为700- 900 kD，含有多个IKK 2和NEMO拷贝。IKKa和IKK两者都含有以下保守的可识别结构域：激酶结构域（KD）、亮氨酸拉链结构域（LZ）、螺旋环螺旋结构域（HLH）和C-末端NEMO结合结构域（NBD）。NEMO包含N-末端激酶结合结构域（KBD）、最小寡聚化结构域（MOD）（其也是泛素结合结构域（UBD））和C-末端锌指结构域（ZF）。IKK和NF-？B信号已经引起了极大的关注，发表了超过30，000篇关于该主题的论文。尽管IKK具有重要的生物学意义，但没有一个成功的结构测定报告，这表明了该项目的难度。为了阐明IKK功能的分子基础并帮助发现IKK抑制剂，我们提出了一系列关于IKK，特别是IKK <$及其调节蛋白NEMO的结构和功能研究。公共卫生相关性：我？B激酶（IKK）是NF-？B活化和许多人类疾病的潜在治疗靶点。该提案寻求IKK的结构研究，这将增强我们对IKK功能的分子基础的理解。此外，拟议的研究将为发现和优化IKK抑制剂治疗炎症性疾病和癌症提供结构基础。