Investigation of the Functional/Folding Landscapes of the Il-1 Family

Il-1 家族功能/折叠景观的研究

• 批准号: 7925103
• 负责人: PATRICIA A JENNINGS
• 金额: $ 19.73万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7925103
• 关键词: Address; Affect; Agonist; Agreement; Autoimmune Diseases; Bacterial Infections; Binding; Biological; Biological Process; Caspase-1; Cleaved cell; Complex; Computational Technique; Coupling; Disease; Docking; Family; Frustration; Funding; Goals; Grant; Inflammatory; Interleukin-1; Interleukin-1 Receptors; Interleukin-1 beta; Interleukin-16; Interleukin-18; Investigation; Kinetics; Link; Membrane; Membrane Proteins; Methodology; Methods; Molecular; Molecular Conformation; Multiprotein Complexes; Play; Post-Translational Protein Processing; Process; Protein Family; Protein Precursors; Proteins; Proteolysis; Reaction; Regulation; Research; Research Personnel; Role; Route; Sampling; Septic Shock; Signal Transduction; Site; Structure; Surface; Techniques; Theoretical Studies; Theoretical model; Time; Travel; Trefoil; Trefoil Family; Trefoil Motif; Work; anakinra; base; cytokine; interest; member; programs; protein folding; receptor; receptor binding; simulation; transmission process

DESCRIPTION (provided by applicant): The principal aim of the previous grant was to use a combination of biophysical and computational techniques to evaluate the key features in the folding/misfolding of the 17 KD beta protein interleukin-1beta (IL-1beta). We have established that the slow folding of this beta-trefoil protein is largely controlled by "topological frustration". During this time period we also became interested in understanding the role conformational dynamics plays in the biological function of this family of proteins. The change in the Title of the grant from "Investigation of the Folding Mechanism of a Beta Protein" to "Investigation of the Functional/Folding Landscapes of the IL-1 Family" reflect this change in research focus. In addition, we have added Dr. Jose Onuchic as a co-Pi on this proposal we have established an integrated experimental/theoretical approach towards the questions we wish to address. It is apparent that the regulation of the processing of IL-1beta is of central importance in bacterial infection and septic shock; autoimmune diseases and some cancers1-8. Yet, little is known about the molecular requirements for processing and maturation of IL-1beta. The goals of the research outlined in this proposal are directed towards (a) investigating the interplay of the functional/folding landscapes within this family of proteins (b) understanding the structural basis for cleavage of the 31 KD precursor protein; (c) the structural characterization of the 31 KD precursor protein and the 24 KD partially cleaved protein; (d) understanding the role of the presequences in destabilizing the fold of the mature 17 KD protein. In summary, our goals are to look at the functional landscapes for related proteins, to develop methods for understanding the receptor binding and signal transmission by analyzing the energy landscapes for the cytokine agonist and antagonist receptor complexes, and exploring the conformational changes that accompany the processing of prolL-1beta from the inactive partially structured state to the active, mature IL-1beta. These studies are of both fundamental importance in understanding protein recognition and activity as well as of fundamental biological importance in understanding the conformational processes that regulate the activation of prolL-1beta.

描述(申请人提供)：上一笔赠款的主要目的是使用生物物理和计算技术相结合的方法来评估17kDβ蛋白白介素1β(IL-1β)折叠/错误折叠的关键特征。我们已经确定这种β-三叶蛋白的缓慢折叠在很大程度上是由“拓扑受挫”控制的。在这段时间里，我们也开始对了解构象动力学在这个蛋白质家族的生物功能中所起的作用感兴趣。该基金的名称从“研究贝塔蛋白的折叠机制”改为“研究IL-1家族的功能/折叠景观”，反映了这一研究重点的变化。此外，我们还增加了Jose Onuchic博士作为这一提议的共同PI。我们已经为我们希望解决的问题建立了一种综合的实验/理论方法。很明显，IL-1β的调节在细菌感染和感染性休克、自身免疫性疾病和一些癌症1-8中起着核心作用。然而，对IL-1β的加工和成熟所需的分子条件知之甚少。本提案中概述的研究目标旨在：(A)研究这一蛋白质家族中功能/折叠环境的相互作用；(B)了解31kD前体蛋白切割的结构基础；(C)31kD前体蛋白和24kD部分切割蛋白的结构特征；(D)了解前序列在破坏成熟17kD蛋白折叠稳定性方面的作用。综上所述，我们的目标是观察相关蛋白质的功能图谱，通过分析细胞因子激动剂和拮抗剂受体复合体的能量图谱，开发了解受体结合和信号传递的方法，并探索伴随Proll-1β从不活跃的部分结构状态到活跃的、成熟的IL-1β的构象变化。这些研究既对理解蛋白质识别和活性具有重要意义，也对了解调节Proll-1β激活的构象过程具有重要的生物学意义。