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 生物分子凝聚物正在成为细胞功能的核心，在各种各样的条件下， 文本.这些缩合物通常具有液体性质，并且由多价聚合物样聚合物组装而成。 分子。总之，这些观察结果表明，一个无序的相互作用网络稳定了 冷凝物。液体系统本质上是无序的，这似乎排除了有序的水平。 结构-功能特性出现的必要条件。然而，初步结果显示， 隐藏在液体无序中的是为UID提供结构的分子组装的层次结构。 此外，接触件内的这种稳定液体的结构赋予了关键的功能特征 到冷凝物。这意味着，为了了解这些冷凝物的功能， 在无序系统中识别结构是必要的。这对结构领域提出了挑战。 因为这种层次结构不能通过X射线，核磁共振， 和冷冻电镜拟议的研究将建立方法来识别和表征结构内 液体冷凝物。这些方法是基于理论建模，使用迭代函数 类似于通过NMR进行结构测定的方法。这将在两个系统中完成，每个系统 在一个特定的目标。rst系统是一种用于相分离的模型系统， 识别和量化相互作用位点的复杂性。在确定显微结构时 这种“贴纸和间隔物”结合系统被认为是液体冷凝器中的常见基序， 这个目标将建立分子结构如何决定空间组织的基本原则 在长度尺度上，从招募分子客户到细胞器分离/共定位。 第二个目标是发展核仁的结构建模技术。这个核细胞器 作为核糖体的装配点。拟议的研究将使用体外相分离数据 了解颗粒组分（GC）中的主要分子相互作用， 和蛋白质组装成核糖体亚基。GC中的相互作用主要是静电作用， 其不同于作为目标1的焦点的贴纸和间隔基序。接下来，这些互动 将用于建立核糖体亚基组装的动力学理论。该模型将确定 GC组分的分子结构促进核糖体组装。两种理论都产生了 目标将是分析性的，这意味着它们将允许彻底探索参数空间， 可以很容易地应用于其他系统。