Dynamics-Function Relationships in Cytochromes c

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。虽然对血红素蛋白结构-功能关系的研究较多，但血红素蛋白动力学与功能之间的关系却很少受到重视。此外，我们对血红素蛋白的氧化还原依赖的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）结构迁移如何调节血红素氧化还原功能。Cyts 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。它们的特点是血红素以共价方式附着在多肽上，通常附着在Cys- x - x -Cys- his基序中的两个Cys残基上。与具有相同血红素辅助因子但缺乏与多肽共价键的Cyts b相比，Cyts c具有更大的电位范围（从-412 mV到+450 mV vs. NHE）。迄今为止，还没有对这种电位范围的变化以及血红素c进入极低电位的能力作出解释。血红素c附着于多肽的方式赋予其独特的结构和动力学性质。本文描述的结构和氧化还原电位的数据提供了一个令人信服的案例，即血红素c的特定性质在氧化还原电位调节中起着重要的间接作用；我们提出c-血红素基序的局部结构和波动调节铁配体相互作用，从而调节氧化还原电位。此外，我们将探讨c-血红素附着如何控制原卟啉IX大环本身的构象，从而有助于氧化还原电位调节。

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.