Repeat Proteins; Stability, Folding Kinetics & Evolution

重复蛋白质；

• 批准号: 8921208
• 负责人: DOUGLAS E. BARRICK
• 金额: $ 31.01万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8921208
• 关键词: Amino Acid Sequence; Ankyrin Repeat; Base Sequence; Biological; Biological Process; Biology; Characteristics; Child; Classification; Classification Scheme; Collection; Communities; Complex; Consensus; Consensus Sequence; Coupling; Databases; Disease; Elements; Entropy; Enzymes; Evolution; Family; Free Energy; Funding; Genes; Goals; Health; Heating; Homeostasis; Instruction; Ising model; Kinetics; Lead; Length; Leucine-Rich Repeat; Maps; Masks; Measures; Membrane; Modeling; Modern Medicine; Molecular Structure; Nature; Pathway interactions; Peptide Sequence Determination; Positioning Attribute; Process; Property; Proteins; Reaction; Reading; Research; Resolution; Route; Series; Signal Transduction; Speed; Structure; Surface; System; Test Result; Testing; Theoretical model; Thermodynamics; Variant; alpha helix; base; beta pleated sheet; biological systems; design; genetic information; globular protein; improved; interfacial; leucine-rich repeat protein; novel; protein aggregation; protein folding; protein misfolding; research study; scaffold; self assembly

DESCRIPTION (provided by applicant): The formation of elaborate molecular structures is a hallmark of biological systems, resulting in enzyme networks, regulatory complexes, membrane signaling and packaging systems, scaffolding networks, and . The instructions for assembly are encoded within the molecules themselves. Understanding how to read these instructions is a major goal in modern biology and in modern medicine, where understanding may lead to rational manipulation of disease mechanisms. One relatively simple yet no less spectacular self-assembly process is the protein folding problem. Understanding the rules, rates, and mechanisms of protein folding would help interpret all aspects of biology, including disease states relating to protein misfolding and aggregation. One of the central features of protein folding is cooperativity. Single-domain proteins fold in all-or-none reactions. This remarkable coupling phenomenon is likely to be important for avoiding misfolded/partly folded states in biology, but it complicates experimental studies of the folding process, masking intermediates, processes, and routes along the way to the native state. The proposed research uses a series of linear symmetric repeat proteins that display all the features of globular proteins, but greatly reduce the complexity of the problem, and allow nearest-neighbor models to be applied to quantify the energetic coupling that underlies cooperativity. This internal symmetry also permits detailed kinetic mechanisms to be tested and parameterized, including parallel pathway nucleation and propagation steps. These modes of analysis will be applied alpha helix and beta sheet containing repeats to measure cooperativity and nucleation kinetic processes and determine their structural origins. Using a recently identified length-variable set of repeats, the size of the repeats and their interfaces with their neighbors will be correlated to cooperativity terms. Further, we will delineate the sequence features that modulate length in this group of proteins, and explore the structural and energetic features of "high-ID repeat protein sequences and their relation to consensus sequences.

描述(申请人提供)：精细分子结构的形成是生物系统的一个标志，导致酶网络、调节复合体、膜信号和包装系统、支架网络和。组装的指令被编码在分子本身中。了解如何阅读这些说明是现代生物学和现代医学的一个主要目标，理解这些说明可能导致对疾病机制的合理操纵。一个相对简单但同样壮观的自组装过程是蛋白质折叠问题。了解蛋白质折叠的规则、速率和机制将有助于解释生物学的各个方面，包括与蛋白质错误折叠和聚集有关的疾病状态。蛋白质折叠的核心特征之一是协作性。单域蛋白在全有或全无反应中折叠。这种显著的耦合现象可能对避免生物学中的错误折叠/部分折叠状态很重要，但它使折叠过程的实验研究复杂化，掩盖了中间体、过程和通往自然状态的路线。拟议的研究使用了一系列线性对称重复蛋白，它们显示了球状蛋白的所有特征，但 降低问题的复杂性，并允许应用最近邻模型来量化作为合作基础的能量耦合。这种内部对称性还允许对详细的动力学机制进行测试和参数化，包括并行路径成核和传播步骤。这些分析模式将被应用于含有重复序列的α螺旋和β折叠，以测量协作性和成核动力学过程，并确定它们的结构来源。使用最近确定的一组长度可变的重复， 重复序列的大小及其与邻居的接口将与协作性项相关联。此外，我们将描述这组蛋白质中调节长度的序列特征，并探索“高ID重复蛋白序列”的结构和能量特征及其与共有序列的关系。