Structure-function properties in liquid organelles

液体细胞器的结构功能特性

• 批准号: 10396101
• 负责人: Jeremy David Schmit
• 金额: $ 31.4万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10396101
• 关键词: Adopted; Architecture; Behavior; Binding; Biochemical; Biogenesis; Biological; Biological Models; Cell Nucleolus; Cell physiology; Cellular Structures; Characteristics; Charge; Client; Complement; Cryoelectron Microscopy; Data; Disease; Electrostatics; Entropy; Evolution; In Vitro; Intervention; Lead; Learning; Length; Link; Liquid substance; Literature; Malignant Neoplasms; Methods; Microscopic; Modeling; Molecular; Molecular Probes; Molecular Structure; Neurodegenerative Disorders; Nuclear; Organelles; Phase; Physical condensation; Polymers; Procedures; Process; Property; Proteins; RNA-Protein Interaction; Research; Ribosomal RNA; Ribosomes; Roentgen Rays; Site; Structural Models; Structure; Structure-Activity Relationship; System; Techniques; Theoretical model; Therapeutic; Work; base; design; driving force; enthalpy; experimental study; in vivo; kinetic theory; molecular assembly/self assembly; recruit; segregation; structural biology; theories; tool

Project Abstract Biomolecular condensates are emerging as central to cellular functions in a wide variety of con- texts. These condensates often have liquid properties and are assembled from multivalent, polymer-like molecules. Together, these observations suggest a disordered network of interactions stabilizing the condensate. Liquid systems are inherently disordered, which would seem to preclude the level of order necessary for structure-function properties to emerge. However, preliminary results have shown that, hidden within the liquid disorder, is a hierarchy of molecular assemblies that give structure to the uid. Furthermore, this structure within the contacts stabilizing the liquid confers crucial functional features to the condensates. This means that in order to understand how these condensates function, it is necessary to identify structure in disordered systems. This poses a challenge to the eld of structural biology because this hierarchical structure cannot be resolved by workhorse techniques like X-ray, NMR, and cryo-EM. The proposed research will establish methods to identify and characterize structure within liquid condensates. These methods are based on theoretical modeling using an iterative re nement procedure analogous to structure determination by NMR. This will be done in two systems that are each featured in a speci c aim. The rst system is a model system for phase separation that removes com- plications with identifying and quantifying interaction sites. In determining the microscopic structure of this \sticker and spacer" binding system, which is thought to be a common motif in liquid conden- sates, this aim will establish basic principles of how molecular structure can dictate spatial organization on lengthscales ranging from the recruitment molecular clients to organelle segregation/colocalization. The second aim will develop the structural modeling techniques on the nucleolus. This nuclear organelle serves as the assembly site for ribosomes. The proposed research will use in vitro phase separation data to understand the primary molecular interactions within the granular component (GC) where rRNAs and protein assemble into ribosomal subunits. The interactions in the GC are primarily electrostatic, which is di erent than the sticker and spacer motif that is the focus of Aim 1. Next, these interactions will be used to build a kinetic theory of ribosome subunit assembly. This model will establish how the molecular structure of GC components facilitates ribosome assembly. The theories for generated in both aims will be analytic, meaning that they will allow for a thorough exploration of parameter space and can be readily applied to other systems.

项目摘要 生物分子冷凝物正在成为细胞功能的核心 文字。这些冷凝水通常具有液体特性，并由多价，聚合物样组装 分子。总之，这些观察结果表明，相互作用的无序网络稳定了 冷凝物。液体系统本质上是无序的，这似乎排除了秩序的水平 结构功能属性所必需的。但是，初步结果表明， 隐藏在液体障碍中的是分子组件的层次结构，这些分子组件为UID提供了结构。 此外，触点内的这种结构稳定液体赋予了重要的功能特征 到冷凝物。这意味着要了解这些冷凝水的功能，它是 确定无序系统中的结构所必需的。这对结构性构成了挑战 生物学，因为这种层次结构无法通过X射线，NMR，NMR，NMR，NMR， 和cryo-em。拟议的研究将建立识别和表征结构内的方法 液体冷凝。这些方法基于使用迭代元素的理论建模 程序类似于NMR的结构测定。这将在两个系统中完成 在特定目标中出现。第一个系统是一个用于相分离的模型系统，可去除com- 识别和量化相互作用位点的平台。在确定微观结构时 该\粘贴和垫片“结合系统 该目标，这个目标将建立分子结构如何决定空间组织的基本原理 从募集分子客户到细胞器隔离/共定位的长度尺度。 第二个目标将在核仁上发展结构建模技术。这个核器官 用作核糖体的装配位点。拟议的研究将使用体外期分离数据 了解颗粒成分（GC）内的主要分子相互作用，其中rrNA 和蛋白质组装成核糖体亚基。 GC中的相互作用主要是静电， 比贴纸和间隔图主题是目标1的不同。接下来，这些相互作用 将用于构建核糖体亚基组装的动力学理论。该模型将确定如何 GC成分的分子结构有助于核糖体组装。两者中生成的理论 目标将进行分析，这意味着它们将允许对参数空间进行彻底探索 可以很容易地应用于其他系统。