Molecular Insights into Membrane Curvature Recognition

膜曲率识别的分子洞察

• 批准号: 8631399
• 负责人: Fang Tian
• 金额: $ 30.43万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8631399
• 关键词: Adopted; Affect; Arginine; Bacillus (bacterium); Bacillus subtilis; Bacteria; Bacterial Spores; Belief; Binding; Biochemical; Biological; Biological Models; Biological Process; Biology; Capsid Proteins; Cell division; Cell physiology; Cells; Cellular Membrane; Cues; DNA Sequence Rearrangement; Data; Detection; Development; Dynamin; Endocytosis; Environment; Escherichia coli; Face; Generations; Geometry; Glycine; Goals; HIV; Human; In Situ; Interdisciplinary Study; Interruption; Lipid Bilayers; Lipids; Location; Maintenance; Mediating; Membrane; Membrane Proteins; Modeling; Molecular; Molecular Conformation; N-terminal; National Cancer Institute; Pennsylvania; Peptides; Peripheral; Phenotype; Process; Proteins; Radial; Regulation; Reproduction spores; Science; Shapes; Solutions; Structural Biologist; Structure; Surface; System; Universities; Vesicle; Viral; Virus; base; epsin; insight; membrane model; molecular dynamics; nanoscale; novel; novel therapeutics; programs; protein structure; protein transport; public health relevance; stoichiometry; trafficking

Abstract We propose to determine the structural and molecular basis of membrane curvature recognition using SpoVM, a highly conserved 26-residue peptide found in Bacillus subtilis (B. subtilis), as a model. During forespore formation, SpoVM exclusively binds to the convex surface of the forespore and initiates the assembly of a protein coat. In 2009, Ramamurthi et al. discovered that SpoVM uses the membrane geometry as an ultimate cue for its final subcellular localization. However, it is unclear how the nanometer-sized SpoVM (~40 ¿ for a presumed ¿-helix) is able to recognize the slightly curved surface of the micrometer-sized forespore. Contrary to the current belief that SpoVM assumes a long straight amphipathic ¿-helix and shallowly associates at the membrane surface, we found that SpoVM adopts a loop-helix structure that is deeply embedded in the membrane. This proposal seeks to extend the study to model systems that are similar in curvature and lipid composition to the membrane of the B. subtilis forespore in order to elucidate the molecular mechanism of SpoVM membrane curvature recognition. We hypothesize that deep hydrophobic insertion is key for SpoVM to detect small membrane curvature. While pursuing these goals, we will exploit geometrically well-defined spherical supported lipid bilayers as a new model for the curved membrane and develop an in situ NMR approach for determining membrane protein structures. The shape of cellular membranes is a well-conserved evolutionary phenotype. Membrane shape is generated and maintained by the interplay of protein-lipid and lipid-lipid interactions. The detection and remodeling of membrane shapes are part of many essential cellular processes such as endocytosis, vesiculation and protein trafficking. Understanding the molecular mechanism for the generation, maintenance, and regulation of membrane geometry is a fundamental question in biology and will open up new therapeutic opportunities.

抽象的 我们建议确定膜曲率识别的结构和分子基础 使用SpoVM（一种在枯草芽孢杆菌（B. subtilis）中发现的高度保守的26个残基肽）作为模型。 在前孢子形成过程中，SpoVM 专门结合到前孢子的凸面并启动 2009 年，Ramamurthi 等人发现 SpoVM 使用膜几何结构。 作为其最终亚细胞定位的最终线索然而，目前尚不清楚纳米尺寸的 SpoVM 是如何实现的。 （~40 ¿ 对于假定的 ¿ 螺旋）能够识别微米尺寸的稍微弯曲的表面 与目前认为 SpoVM 具有长直两亲性的观点相反。 -螺旋和 在膜表面浅缔合，我们发现SpoVM采用环螺旋结构，即 该提案旨在将研究扩展到类似的系统模型。 枯草芽孢杆菌前孢子膜的曲率和脂质组成，以阐明 SpoVM膜曲率识别的分子机制 插入是 SpoVM 检测小膜曲率的关键，在实现这些目标的同时，我们将利用这一点。 几何形状明确的球形支撑脂质双层作为弯曲膜的新模型 开发一种用于确定膜蛋白结构的原位核磁共振方法。 细胞膜的形状是一种高度保守的进化表型。 通过蛋白质-脂质和脂质-脂质相互作用的相互作用产生和维持。 膜形状的重塑是许多重要细胞过程的一部分，例如内吞作用、 了解囊泡形成和蛋白质运输的分子机制。 膜几何形状的调节是生物学中的一个基本问题，并将开辟新的治疗方法 机会。