Structure-Function of Bcl-2 Related Apoptosis Regulators in Membranes

膜中 Bcl-2 相关凋亡调节因子的结构-功能

• 批准号: 8331450
• 负责人: JIALING LIN
• 金额: $ 27.92万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8331450
• 关键词: Address; Apoptosis; Apoptosis Regulator; Apoptotic; Binding; Cell Death; Cells; Characteristics; Chemicals; Complex; Conserved Sequence; Detergents; Development; Dimerization; Disease; Dominant-Negative Mutation; Drug Delivery Systems; Figs - dietary; Fluorescence; Goals; Homo; Homologous Gene; In Vitro; Investigation; Ischemia; Label; Lipids; Liposomes; Malignant Neoplasms; Maps; Mediating; Membrane; Membrane Proteins; Micelles; Mitochondria; Modeling; Molecular; Mutation; Outer Mitochondrial Membrane; Protein Binding; Protein Family; Proteins; Recruitment Activity; Regulation; Research; Series; Site; Solutions; Stroke; Structure; Structure-Activity Relationship; Surface; Techniques; Testing; Therapeutic; Tissues; base; conformational alteration; crosslink; design; effective therapy; genetic regulatory protein; human disease; in vivo; inhibitor/antagonist; insight; next generation; prevent; pro-apoptotic protein; protein complex

DESCRIPTION (provided by applicant): The long-term goal for this project is to elucidate the molecular mechanism for the regulation of programmed cell death. Understanding the mechanism is the key to the development of effective treatments for a wide variety of human diseases such as cancer as ischemia, in which apoptosis is either inhibited or accelerated. The fundamental question we will address is how Bcl-XL and Bax can have opposite functions (anti- and pro- cell death, respectively) yet display similar structures in solution. The specific aims are to determine (1) the structural basis for tBid-activated oligomerization of pro-apoptotic Bax in the mitochondrial outer membrane; and (2) the structural basis for inhibition of tBid-activated Bax by Bcl-XL. To complete the project, we will study the interactions between tBid, Bax and/or Bcl-XL using site-specific cross-linking, chemical labeling and fluorescence techniques. We will also generate mutations in these proteins to elucidate the structure-function relationship. By completing this systematic and thorough investigation, we will generate useful structural information about the membrane-embedded protein complexes, which may facilitate rational design of chemical inhibitors to target either the anti- or the pro-cell death complex for therapeutic benefits.

描述（由申请人提供）：本项目的长期目标是阐明程序性细胞死亡调控的分子机制。了解该机制是开发有效治疗多种人类疾病的关键，例如癌症和缺血，其中细胞凋亡被抑制或加速。我们将解决的基本问题是Bcl-XL和Bax如何具有相反的功能（分别是抗细胞死亡和促细胞死亡），但在溶液中显示出相似的结构。具体目的是确定（1）线粒体外膜中促凋亡Bax的tBid激活寡聚化的结构基础;和（2）Bcl-XL抑制tBid激活Bax的结构基础。为了完成该项目，我们将使用位点特异性交联，化学标记和荧光技术研究tBid，Bax和/或Bcl-XL之间的相互作用。我们还将在这些蛋白质中产生突变，以阐明结构-功能关系。通过完成这一系统和彻底的调查，我们将产生有用的结构信息的膜包埋的蛋白质复合物，这可能有助于合理设计的化学抑制剂的目标无论是抗或促细胞死亡复合物的治疗效益。