Mechanosensing in LIM Domain Proteins

LIM 结构域蛋白中的机械传感

• 批准号: 9259069
• 负责人: Jonathan David Winkelman
• 金额: $ 5.67万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9259069
• 关键词: Actins; Actomyosin; Address; Adherens Junction; Apoptosis; Atherosclerosis; Binding; Binding Sites; Biochemical; Biological Assay; Biotin; Cell Proliferation; Cell division; Cells; Cellular biology; Confocal Microscopy; Cytoskeleton; Decision Making; Defect; Detection; Disease; Distant; Elements; Environment; Extracellular Matrix; Family; Family member; Fiber; Fibroblasts; Focal Adhesions; Heart failure; Human; In Vitro; LIM Domain; LIM Domain Protein; Label; Light; Malignant Neoplasms; Mass Spectrum Analysis; Mechanical Stress; Mechanics; Microfilaments; Modeling; Molecular; Monitor; Myosin ATPase; Myosin Type II; Nature; Pathway interactions; Process; Proteins; Recruitment Activity; Research Project Summaries; Resolution; Rupture; Signal Pathway; Site; Specificity; Streptavidin; Stress; Stress Fibers; Stretching; Structure; System; Testing; Tissues; Translating; ZYX gene; alpha Actinin; blebbistatin; cell behavior; crosslink; experience; experimental study; inhibitor/antagonist; mechanical force; mechanical load; mechanical properties; mechanotransduction; member; organ regeneration; reconstitution; repaired; response; sensor; unnatural amino acids; vasodilator-stimulated phosphoprotein; Actins; Actomyosin; Address; Adherens Junction; Apoptosis; Atherosclerosis; Binding; Binding Sites; Biochemical; Biological Assay; Biotin; Cell Proliferation; Cell division; Cells; Cellular biology; Confocal Microscopy; Cytoskeleton; Decision Making; Defect; Detection; Disease; Distant; Elements; Environment; Extracellular Matrix; Family; Family member; Fiber; Fibroblasts; Focal Adhesions; Heart failure; Human; In Vitro; LIM Domain; LIM Domain Protein; Label; Light; Malignant Neoplasms; Mass Spectrum Analysis; Mechanical Stress; Mechanics; Microfilaments; Modeling; Molecular; Monitor; Myosin ATPase; Myosin Type II; Nature; Pathway interactions; Process; Proteins; Recruitment Activity; Research Project Summaries; Resolution; Rupture; Signal Pathway; Site; Specificity; Streptavidin; Stress; Stress Fibers; Stretching; Structure; System; Testing; Tissues; Translating; ZYX gene; alpha Actinin; blebbistatin; cell behavior; crosslink; experience; experimental study; inhibitor/antagonist; mechanical force; mechanical load; mechanical properties; mechanotransduction; member; organ regeneration; reconstitution; repaired; response; sensor; unnatural amino acids; vasodilator-stimulated phosphoprotein

Project Summary: This research addresses a fundamental question in cell biology: How do cells detect mechanical stress in the actin cytoskeleton? The internal cytoskeletal tension is modulated by the mechanical properties of its external environment. Cytoskeletal tension can be an internal representation the mechanical properties of its local environment that can be “read” by the biochemical machinery. In fact proteins can be stretched by mechanical forces to reveal new binding sites, the recognition of these newly revealed binding sites by “sensor” proteins is one possible way of detecting mechanical information. The LIM superfamily represents a large number of putative mechanosensitive cellular proteins that detect stress by a completely unknown mechanism. I aim to identify the sequence determinants within the LIM domain responsible for detection of mechanical stress in the actin cytoskeleton. I then aim to discover the molecular mechanisms by which LIM domain proteins detect this stress, including identifying what LIM domains bind to and the nature of the deformation in the actin cytoskeleton. Revealing the mechanism of how a single member of this family detects cytoskeletal deformations will likely be generalizable to a large number of proteins. This will also drive future research involving how mechanosensitivity of each LIM protein is tuned and specificity achieved.

项目摘要：本研究解决了细胞生物学的基本问题：细胞如何检测 肌动蛋白细胞骨架中的机械应力？内部细胞骨架张力由机械调节 其外部环境的属性。细胞骨架张力可以是机械的内部表示形式 其本地环境的属性可以由生化机械“读取”。实际上蛋白质可以是 由机械力拉伸以揭示新的结合位点，识别这些新揭示的结合 通过“传感器”蛋白的位点是检测机械信息的一种可能方法。林超家族 代表大量推定的机械敏感细胞蛋白，这些蛋白完全检测到应力 未知机制。我的目的是确定序列在LIM领域内的决定 检测肌动蛋白细胞骨架中的机械应力。然后，我的目标是通过 哪种LIM结构域蛋白检测到这种应力，包括确定LIM域与什么结合和性质 肌动蛋白细胞骨架中的变形。揭示了这个家庭的单个成员的机制 检测细胞骨架变形可能会推广到大量蛋白质。这也会开车 未来的研究涉及如何调整每个LIM蛋白质的机理敏感性并达到特异性。