Molecular mechanism of BCL2-dependent apoptosis

BCL2依赖性细胞凋亡的分子机制

• 批准号: 8856525
• 负责人: DORIT HANEIN
• 金额: $ 75.14万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8856525
• 关键词: Amino Acid Sequence; Apoptosis; Apoptotic; Automobile Driving; BAX gene; BCL-2 Protein; BCL1 Oncogene; BCL2 gene; BID protein; Back; Biological; Cell Death; Cell physiology; Cells; Cellular Structures; Cessation of life; Conflict (Psychology); Cryoelectron Microscopy; Cytoplasm; Detergents; Disease; Environment; Family; Goals; Health; Human; Investigation; Kinetics; Lead; Length; Life; Link; Lipid Bilayers; Malignant Neoplasms; Mediating; Membrane; Mitochondria; Molecular; Molecular Mechanisms of Action; NMR Spectroscopy; Outer Mitochondrial Membrane; Peptide Sequence Determination; Play; Protein Family; Proteins; Relative (related person); Reporting; Running; Signal Transduction; Solubility; Structure; human disease; intermolecular interaction; membrane assembly; mitochondrial membrane; monomer; prevent; protein function; protein structure function; research study; three dimensional structure

DESCRIPTION (provided by applicant): Programmed cell death plays key roles in human health and disease. Signals for cellular life and death are regulated by the BCL-2 family proteins and converge at the mitochondria, where cell fate is ultimately decided. BCL-2 protein activities are critical for maintaining mitochondrial and cellular physiology, and are also linked with major human diseases, especially cancer. Thus, understanding their mechanisms of action has high biomedical priority. The BCL-2 family includes both pro-life (e.g. BCL-XL) and pro-death (e.g. BAX) proteins that exert their regulatory functions through a network of intermolecular interactions as they translocate between the cytoplasm and the mitochondrial outer membrane. Mitochondrial membrane association is a key early step of programmed cell death; however, the exact mechanism through which membrane association mediates BCL-2 protein function is not known. This project focuses on answering the central question: how do the three key BCL-2 relatives, BCL-XL, BAX and BID, transition between soluble and membrane-inserted states to exert their pro- and anti-apoptotic activities?

描述（由申请人提供）：程序性细胞死亡在人类健康和疾病中发挥着关键作用。细胞生命和死亡的信号由 BCL-2 家族蛋白调节，并汇聚于线粒体，细胞命运最终由线粒体决定。 BCL-2 蛋白活性对于维持线粒体和细胞生理机能至关重要，并且还与主要人类疾病，尤其是癌症有关。因此，了解它们的作用机制具有高度的生物医学优先权。 BCL-2 家族包括促生命（例如 BCL-XL）和促死亡（例如 BAX）蛋白，当它们在细胞质和线粒体外膜之间易位时，它们通过分子间相互作用网络发挥其调节功能。线粒体膜结合是程序性细胞死亡的关键早期步骤；然而，膜关联介导 BCL-2 蛋白功能的确切机制尚不清楚。该项目重点回答核心问题：BCL-2 的三个关键亲属 BCL-XL、BAX 和 BID 如何在可溶态和膜插入态之间转变以发挥其促凋亡和抗凋亡活性？