Elucidating the physical mechanisms of membrane fission
阐明膜裂变的物理机制
基本信息
- 批准号:9192596
- 负责人:
- 金额:$ 3.52万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-01 至 2018-08-31
- 项目状态:已结题
- 来源:
- 关键词:Automobile DrivingBindingBinding ProteinsBiologicalBiological AssayC-terminalCell divisionCell physiologyCellsCellular biologyClinicalCrowdingDefectDiabetes MellitusDiseaseDynaminEndocytosisEnsureEnvironmentFamilyGuanosine Triphosphate PhosphohydrolasesHumanHydrophobicityIn VitroKnowledgeLengthLifeLipidsMediatingMembraneMembrane ProteinsMetabolismMissionModelingN-terminalNatureOutcomeOutcomes ResearchPhysiologicalPlayProcessProteinsPublic HealthQuantitative MicroscopyReportingResearchRoleSiteSpecificityStructureSurfaceSystemTestingThinkingTubeViralWorkbasebiophysical toolsconstrictiondensitydisabilityepsinepsin 1improvedinnovationlive cell imagingmutantnervous system disordernovelnovel strategiespathogenpressurepreventquantitative imagingresearch studytooltrafficking
项目摘要
Project Summary. The separation of membranes into discrete compartments through the process of
membrane fission is essential for diverse cellular processes ranging from cell division to viral entry. While the
specialized fission machine dynamin is well-known to induce fission through constriction of membrane tubes,
recent evidence shows that other proteins drive fission by previously unknown mechanisms. In particular, the
epsin 1 N-terminal homology (ENTH) domain is a potent driver of membrane curvature (Ford et al., Nature
2002), and has recently been shown to play a role in membrane fission. Specifically, a recent report proposed
that insertion of a wedge-like amphipathic helix by ENTH curves and destabilizes membranes, as evidenced by
decreasing membrane fission ability among ENTH mutants with decreasing helix hydrophobicity (Boucrot et al.,
Cell 2012). However, our group recently showed that collisions among dense, membrane-bound ENTH
proteins generate steric pressure, which drives membrane bending in the absence of helix insertions
(Stachowiak et al., Nature Cell Biology 2012). These results prompted us to ask: is steric pressure also
responsible for membrane fission by ENTH? In my preliminary studies, I found that ENTH mutants with
reduced helix hydrophobicity are capable of driving fission to a similar degree as wild-type ENTH when bound
to the membrane at comparable density. Interestingly, I also found that full-length epsin, which contains a bulky,
intrinsically-disordered C-terminal domain, drives fission more potently than the ENTH domain alone. These
results imply that, while helix insertions are important for binding proteins tightly to membrane surfaces, helices
are not required for fission. However, once bound to the membrane surface at sufficient density, bulky
molecules of arbitrary structure can create steric pressure that increases membrane curvature until fission
occurs. Taken together, my findings reveal a novel mechanism for membrane fission. The objective of the
proposed research is to quantitatively compare this new mechanism with other key mechanisms of membrane
fission. The first specific aim will delineate the specific roles of wedge-like helix insertion and protein crowding
in driving membrane fission. The second specific aim will examine how dynamin works cooperatively with helix
insertion and protein crowding to drive robust fission. The third specific aim will utilize quantitative imaging of
live cells to examine how helix insertion and protein crowding modulate fission dynamics in a physiological
context. This work will create innovative biophysical tools for the simultaneous study of membrane fission and
protein-lipid interactions both in vitro and in live cells. The overall outcome of this research will be a deeper
understanding of the physical mechanisms of membrane fission, including the novel mechanism of membrane
fission by protein crowding. The bold hypothesis described here asserts that any membrane-bound protein can
contribute to fission, an idea that will influence understanding of diverse membrane compartmentalizing
processes, including endocytosis, cell division, and viral entry.
项目摘要。通过整个过程将膜分离为离散隔室
膜裂变对于从细胞分裂到病毒的各种细胞过程至关重要。而
专门的裂变机元素众所周知,可以通过收缩膜管诱导裂变,
最近的证据表明,其他蛋白质通过以前未知的机制驱动裂变。特别是
Epsin 1 N末端同源性(ENTH)结构域是膜曲率的有效驱动力(Ford等,自然
2002年),最近已显示出在膜裂变中发挥作用。特别是,最近提出的一份报告
通过Enth Curves插入类似楔形的两体性螺旋并破坏膜的插入,这证明了
在螺旋疏水性降低的源头突变体之间降低膜裂变能力(Boucrot等,,,
细胞2012)。但是,我们的小组最近表明,密集的,膜结合的源头发生冲突
蛋白质会产生空间压力,在没有螺旋插入的情况下驱动膜弯曲
(Stachowiak等人,自然细胞生物学2012)。这些结果促使我们问:也是空间压力
负责ENTH的膜裂变?在我的初步研究中,我发现
当结合时,降低的螺旋疏水性能够将裂变与野生型率相似
以相当的密度到膜。有趣的是,我还发现包含笨重的全长Epsin,
本质上排出的C末端结构域比单独的enth域更有效地裂变。这些
结果表明,尽管螺旋插入对于将蛋白紧密结合到膜表面,但螺旋螺旋很重要
不需要裂变。但是,一旦以足够的密度结合到膜表面
任意结构的分子可以产生空间压力,从而增加膜曲率直到裂变
发生。综上所述,我的发现揭示了一种新的膜裂变机制。目的
拟议的研究是定量将这种新机制与膜的其他关键机制进行比较
裂变。第一个特定目的将描述楔形螺旋插入和蛋白质拥挤的特定作用
在驱动膜裂变中。第二个特定目的将研究Dynamin与螺旋的合作方式
插入和蛋白质拥挤以驱动稳定的裂变。第三个特定目的将利用定量成像
活细胞检查螺旋插入和蛋白质拥挤如何在生理中调节裂变动力学
语境。这项工作将创建创新的生物物理工具,用于同时研究膜裂变和
蛋白质脂质相互作用在体外和活细胞中均可进行。这项研究的总体结果将更深入
了解膜裂变的物理机制,包括膜的新机制
蛋白质拥挤的裂变。这里描述的大胆假设断言,任何膜结合的蛋白都可以
有助于裂变,这将影响对各种膜分隔的理解的想法
过程,包括内吞作用,细胞分裂和病毒。
项目成果
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Wilton Thomas Snead其他文献
Wilton Thomas Snead的其他文献
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{{ truncateString('Wilton Thomas Snead', 18)}}的其他基金
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细胞表面作为生物分子凝聚体组装的调节剂
- 批准号:
10639551 - 财政年份:2023
- 资助金额:
$ 3.52万 - 项目类别:
Regulatory mechanisms of protein and RNA phase transitions
蛋白质和RNA相变的调控机制
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- 资助金额:
$ 3.52万 - 项目类别:
Regulatory mechanisms of protein and RNA phase transitions
蛋白质和RNA相变的调控机制
- 批准号:
9910707 - 财政年份:2020
- 资助金额:
$ 3.52万 - 项目类别:
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