Increasing the Complexity of Microtubule-based transport: Cargo adaptors and Hitchhiking on Vesicles.

增加基于微管的运输的复杂性：货物适配器和囊泡搭便车。

• 批准号: 10713449
• 负责人: JOHN SALOGIANNIS
• 金额: $ 39万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713449
• 关键词: Adaptor Signaling Protein; Address; Affect; Binding; Biochemistry; Biological Models; Cell physiology; Defect; Development; Disease; Dynein ATPase; Eukaryotic Cell; Genetic; Goals; Growth; Kinesin; LRRK2 gene; Link; Membrane; Microscopy; Microtubules; Molecular; Molecular Motors; Motor; Movement; Mutation; Neurodegenerative Disorders; Neurodevelopmental Disorder; Organelles; Parkinson Disease; Phosphorylation Site; Phosphotransferases; Play; Positioning Attribute; Research; Role; Site; Specificity; Vesicle; age related; cell growth; macromolecule; malignant neurologic neoplasms; nervous system disorder; organelle movement; rab GTP-Binding Proteins; recruit; trafficking

PROJECT SUMMARY Proper positioning of intracellular cargos (organelles, vesicles, and macromolecules) is critical for cell growth, maturation, and survival. Eukaryotic cells use the molecular motors dynein and kinesin to transport cargos along microtubule tracks. Defects in microtubule-based transport and mutations in the motors themselves, are an underlying feature of many neurodevelopmental and neurodegenerative diseases. Since each type of cargo is tuned for specific cellular functions, their loading, movement and unloading along microtubules requires divergent transport mechanisms. How is cargo specificity on microtubules achieved? This proposal will address this with an in-depth analysis of the two major modes of microtubule-based transport. The canonical view, known as the cargo adaptor mode, is that each cargo interacts with specific adaptor proteins capable of recruiting molecular motors. The regulatory mechanisms by which cargos selectively load and unload from these cargo adaptors are not well understood. One goal of this proposal is to determine how a conserved phosphorylation site on vesicle-bound Rab GTPases affects interactions with dynein cargo adaptors and ultimately, how these interactions affect cellular function. Importantly, this Rab phosphorylation site is the predominant target of the Parkinson’s disease-linked kinase LRRK2. The other mode of transport is called organelle hitchhiking. In hitchhiking, Rab-vesicles can direct the movement of organelles on microtubules. To accomplish this, organelles attach to (or ‘hitchhike’ on) motor-driven Rab-vesicles at membrane contact sites. Organelle hitchhiking is a new, relatively unexplored paradigm of microtubule-based transport, and the underlying molecular mechanisms are not well understood. What are the molecular linkers, tethers, and regulators of organelle hitchhiking? Is this a prominent mode of microtubule-based transport? This proposal will use genetics, microscopy, and biochemistry in both fungal and mammalian model systems to address these questions. Taken together, studying the two main modes of microtubule-based transport is extremely important, given the critical roles Rabs, vesicles, and hitchhiking cargos play in development and age-related diseases.

项目总结