Dynamics-Function Relationships in Cytochromes c

细胞色素 c 中的动力学与功能关系

• 批准号: 7591074
• 负责人: KARA L. BREN
• 金额: $ 24.73万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7591074
• 关键词: Aging; Amino Acids; Archaea; Attention; Bacteria; Binding Proteins; Biogenesis; Biological; Biological Models; Biological Process; Catalysis; Cell Death; Cells; Chemistry; Chloroplasts; Complex; Cytochromes; Data; Development; Disease; Distal; Electron Transport; Environment; Event; Goals; Health; Heme; Hemeproteins; Human; Iron; Lead; Ligand Binding; Ligands; Ligation; Link; Methods; Mitochondria; Modeling; Molecular Conformation; Oxidation-Reduction; Phase; Play; Positioning Attribute; Process; Property; Propionates; Protein Dynamics; Proteins; Reactive Oxygen Species; Relative (related person); Research Personnel; Role; Science; Signal Transduction; Solutions; Source; Structure; Structure-Activity Relationship; Testing; Variant; aqueous; biophysical chemistry; cofactor; covalent bond; cytochrome c; flexibility; heme a; interest; iron protoporphyrin IX; meetings; methionylmethionine; novel; polypeptide; programs; protoporphyrin IX

DESCRIPTION (provided by applicant): Oxidation/reduction (redox) chemistry of iron-protoporphyrin IX (heme) is central to many fundamental biological processes including energy transduction, redox catalysis, sensing, and signaling. Although there have been many studies of structure-function relationships in heme proteins, the relationship between heme protein dynamics and function has received little attention. In addition, our understanding of how redox- dependent biophysical properties of heme proteins impact electron transfer is not well developed. In this project, we will investigate how cytochrome c (cyt c) structural mobility modulates heme redox function. Cyts c are ubiquitous proteins displaying a range of redox-related functions. They are characterized by the covalent means of heme attachment to the polypeptide, usually to two Cys residues in a Cys-X-X-Cys-His motif. Cyts c span a larger range of potentials (from -412 to +450 mV vs. NHE) relative to cyts b (-130 to +390 mV vs. NHE), which have the same heme cofactor but lack covalent bonds to the polypeptide. To date, an explanation for this variation in range of potentials, and the ability of heme c to access extremely low potentials, has not been made. The means of attachment of heme c to the polypeptide impart on it unique structural and dynamical properties. Data on structure and redox potential described herein present a compelling case that the specific properties of heme c play an important if indirect role in redox potential tuning; we propose that the local structure and fluctuations about the c-heme motif tune iron-ligand interactions and thus redox potential. In addition, we will explore how control of the conformation of the protoporphyrin IX macrocycle itself by the c-heme attachment contributes to redox potential tuning. Cytochromes play vital roles in energy transduction in mitochondria, bacteria, and chloroplasts, as well as many archaea. Such processes are a significant source of reactive oxygen species (ROS), which are a major contributing factor to diseases associated with aging. To develop a complete understanding of events contributing to aging and cell death, and to the development and progression of a range of diseases, the fundamentals of redox chemistry in the cell must be understood. Elucidating basic mechanisms controlling biological redox chemistry is therefore of fundamental importance to biomedical sciences and human health.

描述（由申请人提供）：铁-原卟啉IX（血红素）的氧化/还原（氧化还原）化学是许多基本生物过程的核心，包括能量转导、氧化还原催化、传感和信号传导。虽然已经有很多关于血红素蛋白的结构-功能关系的研究，但是血红素蛋白动力学和功能之间的关系很少受到关注。此外，我们对血红素蛋白的氧化还原依赖性生物物理性质如何影响电子转移的理解还没有很好地发展。在这个项目中，我们将研究细胞色素c（cyt c）的结构迁移率如何调节血红素的氧化还原功能。细胞色素c是一种普遍存在的蛋白质，具有一系列氧化还原相关的功能。它们的特征在于血红素与多肽的共价连接方式，通常是与Cys-X-X-Cys-His基序中的两个Cys残基连接。相对于细胞B（相对于NHE为-130至+390 mV），细胞C的电位范围更大（相对于NHE为-412至+450 mV），细胞B具有相同的血红素辅因子，但缺乏与多肽的共价键。迄今为止，尚未对这种电位范围的变化以及血红素C获得极低电位的能力作出解释。血红素c与多肽的连接方式赋予其独特的结构和动力学性质。本文所述的结构和氧化还原电位的数据提出了一个令人信服的情况下，血红素c的具体性质发挥重要的，如果在氧化还原电位调谐间接的作用，我们建议，当地的结构和波动的c-血红素基序调整铁-配体的相互作用，从而氧化还原电位。此外，我们将探讨如何控制的构象的原卟啉IX大环本身的c-血红素附件有助于氧化还原电位调谐。 细胞色素在线粒体、细菌和叶绿体以及许多古细菌的能量传递中起着至关重要的作用。这些过程是活性氧（ROS）的重要来源，活性氧是与衰老相关的疾病的主要促成因素。为了全面了解导致衰老和细胞死亡的事件，以及一系列疾病的发展和进展，必须了解细胞中氧化还原化学的基本原理。因此，阐明控制生物氧化还原化学的基本机制对生物医学科学和人类健康具有根本的重要性。