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Thermodynamics and kinetics of iso-1-cytochrome c denatured state.

机译：iso-1-细胞色素c变性状态的热力学和动力学。

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摘要

Various diseases result from protein misfolding. Curing these conditions requires understanding the principles governing folding. Efforts toward understanding how proteins fold have focused on the transition state rather than the earliest folding events. We study these initial events using the assumption that protein folding must involve the formation of the most primitive structure possible -- a simple loop. Our laboratory has developed a system of studying simple loops in the denatured state using c-type cytochromes. New insights into how the properties of these loops impact the denatured state are outlined in this thesis.;First, studies on a 22-residue loop revealed a previously unreported finding that equilibrium loop formation was not strongly affected by sequence composition. While loop formation rates depended only on sequence composition, loop breakage rates also depended on sequence order. Second, thermodynamic and kinetic studies on homopolymeric inserts in "poor" and "good" solvents revealed that homopolymeric non-foldable protein sequences behave like a random coil. However, heteropolymeric foldable sequences have scaling factors higher than those of a random coil, suggesting the presence of residual structure in denatured proteins. Thus, peptide models with homopolymeric sequences do not adequately describe the nature of foldable sequences. Third, we investigated the kinetics of reversible oligomerization in the denatured state using a P25A yeast iso-1-cytochrome c variant. The findings indicated that intermolecular aggregation in a denatured protein is extremely fast -- 107-108 M-1s-1 and that the P25A mutation strongly affects intermolecular aggregation. This work suggests that equilibrium control of folding versus aggregation is advantageous for productive protein folding in vivo. Fourth, we use time-resolved FRET to follow compact and extended distributions of a protein under denaturing conditions. Our findings revealed three major populations in the unfolded state when no loop is present whereas only two populations remain when the loop forms. The most extended population is lost upon loop formation showing that simple loop formation dramatically constrains the denatured state.;Thus, thermodyamic and kinetic studies on simple loops using a variety of spectroscopic techniques have enhanced understanding of the initial events of protein folding and the role of the denatured state in modulating protein aggregation.
机译：蛋白质错误折叠会导致多种疾病。固化这些条件需要了解控制折叠的原理。理解蛋白质如何折叠的努力集中于过渡状态，而不是最早的折叠事件。我们使用蛋白质折叠必须涉及可能的最原始结构的形成-一个简单的循环-的假设来研究这些初始事件。我们的实验室开发了使用c型细胞色素研究变性状态下简单环的系统。本文概述了对这些环的性质如何影响变性状态的新见解。首先，对22个残基的环的研究表明，以前没有报道发现平衡环的形成不受序列组成的强烈影响。环形成速率仅取决于序列组成，而环断裂速率也取决于序列顺序。其次，对“不良”和“良好”溶剂中均聚物插入物的热力学和动力学研究表明，均聚物不可折叠的蛋白质序列表现得像无规卷曲。但是，杂聚合折叠序列的缩放因子高于随机线圈的缩放因子，表明变性蛋白质中存在残留结构。因此，具有均聚物序列的肽模型不能充分描述可折叠序列的性质。第三，我们研究了使用P25A酵母iso-1-cytochrome c变体在变性状态下可逆寡聚的动力学。这些发现表明变性蛋白质中的分子间聚集非常快-107-108 M-1s-1，并且P25A突变强烈影响分子间聚集。这项工作表明折叠与聚集的平衡控制对于体内生产性蛋白质折叠是有利的。第四，我们使用时间分辨的FRET来跟踪变性条件下蛋白质的紧密和扩展分布。我们的发现表明，当不存在回路时，三个主要种群处于未折叠状态，而当回路形成时，仅剩下两个种群。环形成后失去的最广泛种群表明简单的环形成极大地限制了变性状态。因此，使用各种光谱技术对简单环的热力学和动力学研究已加深了对蛋白质折叠的初始事件及其作用的理解。调节蛋白质聚集的变性状态。

著录项

  • 作者

    Tzul, Franco Ollan.;

  • 作者单位

    University of Montana.;

  • 授予单位 University of Montana.;
  • 学科 Chemistry Biochemistry.;Biophysics General.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 232 p.
  • 总页数 232
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;生物物理学;
  • 关键词

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