THE STRUCTURAL BASIS FOR THE ASSEMBLY AND REGULATION OF THE MLL CORE COMPLEX

MLL 核心复合体组装和调节的结构基础

• 批准号: 8363528
• 负责人: Michael S. Cosgrove
• 金额: $ 0.76万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8363528
• 关键词: Acute leukemia; Amino Acids; Antineoplastic Agents; Binding; Binding Sites; Biological; Complex; DNA Sequence Rearrangement; Data; Development; Epigenetic Process; Funding; Goals; Grant; Hematopoiesis; Histone H3; Homeobox Genes; Human; Investigation; Lysine; MLL gene; Macromolecular Complexes; Maps; Methylation; Molecular; Mono-S; Myeloid-Lymphoid Leukemia Protein; National Center for Research Resources; Oncogenic; Outcome; Peptides; Principal Investigator; Proteins; Regulation; Research; Research Infrastructure; Resolution; Resources; Role; SET Domain; Site; Source; Specificity; Structural Protein; Structure; United States National Institutes of Health; base; cost; design; histone methyltransferase; leukemia; outcome forecast; protein complex; protein protein interaction; Acute leukemia; Amino Acids; Antineoplastic Agents; Binding; Binding Sites; Biological; Complex; DNA Sequence Rearrangement; Data; Development; Epigenetic Process; Funding; Goals; Grant; Hematopoiesis; Histone H3; Homeobox Genes; Human; Investigation; Lysine; MLL gene; Macromolecular Complexes; Maps; Methylation; Molecular; Mono-S; Myeloid-Lymphoid Leukemia Protein; National Center for Research Resources; Oncogenic; Outcome; Peptides; Principal Investigator; Proteins; Regulation; Research; Research Infrastructure; Resolution; Resources; Role; SET Domain; Site; Source; Specificity; Structural Protein; Structure; United States National Institutes of Health; base; cost; design; histone methyltransferase; leukemia; outcome forecast; protein complex; protein protein interaction

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The Mixed Lineage Leukemia (MLL) protein catalyzes histone H3 lysine 4 (H3K4) methylation, which is an epigenetic mark essential for the regulation of HOX genes in hematopoiesis and development. Translocations that disrupt the MLL gene are present in a unique group of acute leukemias, often predicting a poor prognosis. Other MLL rearrangements and amplifications increase MLL's enzymatic activity and are oncogenic. MLL contains an evolutionarily conserved ~130 amino acid SET domain that catalyzes H3K4 methylation. Recent studies indicate that the enzymatic activity of MLL is regulated by a conserved complex of proteins including WDR5, RbBP5, and ASH2L. These proteins form an independent complex that binds to MLL and regulates MLL's ability to mono-, di-, or trimethylate H3K4, a phenomenon known as 'Product Specificity'. Since different levels of methylation of H3K4 are associated with different transcriptional outcomes, it is imperative to understand the molecular mechanisms by which the product specificity of MLL is regulated. Despite the important biological role of MLL and its involvement in human leukemia, there is currently little information about the protein-structural features that are responsible for the enzymatic activity of MLL. The long-term goal of this research is to fully characterize the histone methyltransferase activity of MLL to facilitate the identification and rational design of new anti-cancer drugs for the treatment of human leukemias. This proposal takes a structure-function approach to investigate the molecular mechanisms of MLL SET domain regulation by protein-protein interactions. We have mapped the site of interaction between MLL and WDR5, and have obtained crystals of WDR5 with a peptide derived from MLL. The initial structure diffracted to 1.72 angstroms, and elucidtaed the peptide binding site. For this investigation, we would like to obtain higher resolution data with a longer peptide to determine if other interactions between MLL and WDR5 are important.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 混合谱系白血病（MLL）蛋白催化组蛋白H3赖氨酸4（H3K4）甲基化，这对于调节造血和发育中HOX基因的表观遗传标记必不可少。破坏MLL基因的易位存在于独特的急性白血病中，通常预测预后不佳。 其他MLL重排和扩增会增加MLL的酶活性，并且具有致癌性。 MLL包含一个催化H3K4甲基化的进化保守的〜130个氨基酸套件。 最近的研究表明，MLL的酶活性受到蛋白质的保守络合物（包括WDR5，RBBP5和ASH2L）的调节。这些蛋白质形成独立的复合物，与MLL结合并调节MLL的单，二甲基酸H3K4的能力，这是一种称为“产品特异性”的现象。由于H3K4的不同水平与不同的转录结果有关，因此必须了解MLL的产品特异性的分子机制。尽管MLL及其参与人白血病的重要生物学作用，但目前几乎没有关于蛋白质结构特征的信息，这些特征是导致MLL酶促活性的。这项研究的长期目标是充分表征MLL的组蛋白甲基转移酶活性，以促进新抗癌药物的鉴定和合理设计，以治疗人类白血病。 该建议采用一种结构功能方法来研究通过蛋白质 - 蛋白质相互作用调节MLL集域调节的分子机制。我们已经绘制了MLL和WDR5之间的相互作用位点，并获得了WDR5的晶体，该晶体具有衍生自MLL的肽。初始结构衍射为1.72埃，并阐明了肽结合位点。对于这项研究，我们希望获得具有更长肽的更高分辨率数据，以确定MLL和WDR5之间的其他相互作用是否重要。