Information Processing by Post-translational Modification

通过翻译后修饰进行信息处理

基本信息

批准号：
10430115
负责人：
JEREMY GUNAWARDENA
金额：
$ 36.62万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10430115
关键词：
ADP ribosylation Acetylation Address Affect Alzheimer&apos 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 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 Proteins Recombinants Role Site Software Tools 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

项目摘要

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这种“翻译后修饰”（PTM）允许蛋白质发挥功能。 PTM 参与调节大多数细胞过程。一种蛋白质具有多种类型并不少见。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位点组合相互作用以影响蛋白质功能，这可能会导致蛋白质的爆炸。组合修饰指出，该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 个组合的潜力这种单一蛋白质上的修饰状态很少会在任何时候出现，但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我们之前的工作已经为解决这些问题奠定了基础。引入了“modforms”和“modform distributions”的定量语言，它提供了我们创建了描述体内 PTM 状态的严格生物物理学基础。用于分析可以测量此类分布的质谱（MS）方法我们已经表明了“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 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。我们开发了可公开访问的软件来估计此类数据。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在这里，我们与经过测试的多学科小组建立了这些发现。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。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。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Nac1 Coordinates a Sub-network of Pluripotency Factors to Regulate Embryonic Stem Cell Differentiation.

Nac1 协调多能因子子网络来调节胚胎干细胞分化。

DOI：
10.1016/j.celrep.2015.12.101
发表时间：
2016-02-09
期刊：
Cell reports
影响因子：
8.8
作者：
Malleshaiah M;Padi M;Rué P;Quackenbush J;Martinez-Arias A;Gunawardena J
通讯作者：
Gunawardena J

Time-series transcriptomics and proteomics reveal alternative modes to decode p53 oscillations.

时间序列转录组学和蛋白质组学揭示了解码 p53 振荡的替代模式。

DOI：
发表时间：
2022-03
期刊：
影响因子：
9.9
作者：
Jiménez, Alba;Lu, Dan;Kalocsay, Marian;Berberich, Matthew J;Balbi, Petra;Jambhekar, Ashwini;Lahav, Galit
通讯作者：
Lahav, Galit

Estimating the Distribution of Protein Post-Translational Modification States by Mass Spectrometry.

通过质谱法估计蛋白质翻译后修饰状态的分布。