Information Processing by Post-translational Modification

通过翻译后修饰进行信息处理

• 批准号: 9817314
• 负责人: JEREMY GUNAWARDENA
• 金额: $ 38.36万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9817314
• 关键词: ADP ribosylation; Acetylation; Address; Affect; Alzheimer' s Disease; Amino Acids; Biochemical; Biological Process; Biophysics; Cell physiology; Cellular biology; Chemicals; Code; Collaborations; Computer software; Computing Methodologies; DNA Double Strand Break; Data; Disease; Etiology; Exhibits; Explosion; Foundations; Genome; Goals; Grant; Home environment; In Vitro; Language; Learning; Malignant Neoplasms; Mass Spectrum Analysis; Mathematics; Measures; Methodology; Methods; Methylation; Modification; Molecular; Molecular Biology; Organism; Pathway interactions; Pattern; Peptides; Phosphorylation; Physiologic pulse; Physiological; Play; Population; Post-Translational Protein Processing; Process; Protein p53; Proteins; Recombinants; Role; Site; Software Tools; Structural Protein; TP53 gene; Technology; Testing; Time; Tumor Suppressor Proteins; Ubiquitination; Work; base; chemical group; combinatorial; gamma irradiation; genetic regulatory protein; high dimensionality; in vivo; information processing; insight; mathematical methods; mathematical model; multidisciplinary; protein function; protein structure; response; single molecule

Summary/Abstract Most proteins in an organism are reversibly modified by covalent attachment of chemical groups to specific amino-acid residues. Such “post-translational modification” (PTM) allows protein function to be modulated on a physiological time-scale. PTMs are involved in regulating most cellular processes and frequently disordered in major diseases. It is not uncommon for a protein to have many types of modification, for these to occur on multiple sites across the protein and for modifications on different sites to interact combinatorially to influence protein function. This can create an explosion of combinatorial modification states. The tumor suppressor p53, on which this proposal will focus, has more than 100 sites of modification, creating the potential for more than 1030 combinatorial modification states on this single protein. Very few of these states will be present at any time but that leaves open the question of which states are present and how they vary under different cellular conditions. Our previous work has laid a foundation for addressing these questions. We have introduced the quantitative language of “modforms” and “modform distributions”, which provide a rigorous biophysical basis for describing PTM states in vivo. We have created mathematical methods for analyzing the mass-spectrometry (MS) approaches which can measure such distributions and have determined their fundamental limits. We have shown the necessity of combining “bottom-up” and “middle-down” MS, in which proteins are first digested in peptides, with “top-down” MS on whole proteins. These different types of MS data constrain a protein's modform distribution within a high- dimensional “modform region”. We have developed publicly-accessible software for estimating such regions. We have discovered that p53 integrates its pulsatile expression dynamics and its PTM state to act as a central cellular hub and orchestrate multiple downstream pathways in response to multiple upstream conditions. Here, we build on these findings with a tested multi-disciplinary group of collaborators, whose expertise spans mathematics, computation, cell biology and mass spectrometry. Our goal is to develop MS methods to estimate modform regions of typical cellular proteins and to use those methods to unravel how p53 combines dynamics and modforms to process information. By focusing on such a challenging exemplar, we expect to learn a great deal about p53 itself while developing concepts and methods that can be widely applied to other cellular proteins in which PTMs play a central role.

摘要/摘要 生物体中的大多数蛋白质通过化学基团的共价连接而被可逆地修饰 特定的氨基酸残基。这种“翻译后修饰”（PTM）允许蛋白质功能 在生理时间尺度上进行调节。 PTM 参与调节大多数细胞过程 且常因重大疾病而紊乱。蛋白质具有多种类型的情况并不罕见 修饰，这些修饰发生在蛋白质的多个位点上以及不同的修饰上 组合相互作用以影响蛋白质功能的位点。这可能会造成爆炸 组合修饰状态。本提案将重点关注的肿瘤抑制因子 p53 具有 超过 100 个修饰位点，创造了超过 1030 个组合的潜力 该单一蛋白质的修饰状态。这些状态中很少有任何时候都会出现，但是 存在哪些状态以及它们在不同细胞下如何变化的问题仍然悬而未决 状况。我们之前的工作为解决这些问题奠定了基础。我们有 引入了“modforms”和“modform distributions”的定量语言，它提供了 描述体内 PTM 状态的严格生物物理学基础。我们创造了数学方法 用于分析可以测量此类分布的质谱（MS）方法 已经确定了它们的基本极限。我们已经证明了“自下而上”和“自下而上”相结合的必要性。 “中下”MS，其中蛋白质首先被消化成肽，整体上是“自上而下”MS 蛋白质。这些不同类型的 MS 数据将蛋白质的修饰形式分布限制在高范围内。 维度“修改区域”。我们开发了可公开访问的软件来估计此类 地区。我们发现 p53 整合了其脉冲表达动力学及其 PTM 状态 充当中央细胞枢纽并协调多个下游途径以响应多个 上游条件。在这里，我们通过经过测试的多学科小组建立在这些发现的基础上 合作者，其专业知识涵盖数学、计算、细胞生物学和质谱。 我们的目标是开发 MS 方法来估计典型细胞蛋白质的修饰区域并使用 这些方法揭示了 p53 如何结合动力学和 modform 来处理信息。经过 专注于这样一个具有挑战性的范例，我们希望能够深入了解 p53 本身，同时 开发可广泛应用于其他细胞蛋白的概念和方法，其中 PTM 发挥核心作用。