Development of functional synthetic biomolecular condensates.

功能性合成生物分子缩合物的开发。

基本信息

批准号：
10880846
负责人：
Allie C Obermeyer
金额：
$ 10.15万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-08-31
项目状态：
未结题

项目摘要

PROJECT SUMMARY Membraneless organelles, or biomolecular condensates, have emerged as a strategy to organize the contents of prokaryotic and eukaryotic cells. These phase separated compartments play key roles in a range of cellular functions – from signaling to tuning metabolic pathways or controlling gene expression – yet there are still questions about the fundamental mechanisms for their formation, dynamics, and function. The relationship between condensate molecular properties and function is not yet understood, but this could provide an avenue to treat diseases that involve dysregulated protein condensates (neurodegeneration, cataracts, cancer). Our research proposes to develop functional synthetic biomolecular condensates in order to address several over- arching questions: How do specific intermolecular interactions (electrostatic, cation-π, etc.) contribute to protein phase transitions? How do protein sequence and structure influence the physical properties and function of the condensed phase? Is there a connection between the materials properties and the function of biomolecular condensates? Semi-synthetic biomolecular condensates will allow us to evaluate how molecular interactions in the condensed phase contribute not only to the dynamics of the phase but also to small and macromolecule partitioning, and ultimately the function of endogenous biomolecular condensates. The goals of the proposed research program are to create enzymatically active synthetic membraneless organelles in vitro and in vivo. New materials with varied chemical environments will be prepared and new methods for imaging protein condensates at the molecular scale will be established. These advances will help us to understand how protein sequence influences function at both the microscale (e.g. of an individual enzyme) and the mesoscale (e.g. of a condensed phase cellular compartment). Engineering orthogonal biomolecular condensates has the potential to impact our understanding of the function of native biomolecular condensates and provide a synthetic biology platform to artificially regulate information flow in the cell.

项目摘要膜无细胞器或生物分子冷凝物已成为组织内容的策略原核细胞和真核细胞。这些相分离的隔室在一系列细胞中起关键作用功能 - 从信号到调整代谢途径或控制基因表达的功能 - 但仍有有关其形成，动态和功能的基本机制的问题。关系在冷凝水分子特性和功能之间尚不清楚，但这可以提供途径治疗涉及失调蛋白质冷凝物（神经退行性，白内障，癌症）的疾病。我们的为了解决几个过度 - 拱门问题：特定分子间相互作用（静电，阳离子-π等）如何有助于蛋白质相变？蛋白质序列和结构如何影响凝结阶段？材料特性与生物分子的功能之间是否存在联系冷凝水？半合成生物分子冷凝物将使我们能够评估分子相互作用如何凝结相不仅有助于该相的动力学，而且对小分子和大分子也有贡献分配，最终是内源性二分子冷凝物的功能。提议的目标研究计划将在体外和体内创建酶活性的合成无膜细胞器。新的将准备具有不同化学环境的材料，并成像蛋白质冷凝物的新方法将在分子量表上建立。这些进步将有助于我们了解蛋白质序列在显微镜（例如单个酶）和中尺度（例如凝结的酶）上影响功能相细胞室）。工程正交的生物分子冷凝水有可能影响我们的了解天然生物分子冷凝物的功能，并为人为调节细胞中的信息流。