Role of the Sec1p/Munc18 (SM) protein Vps45p in SNARE complex assembly and bilayer fusion

Sec1p/Munc18 (SM) 蛋白 Vps45p 在 SNARE 复合物组装和双层融合中的作用

• 批准号: BB/E024904/1
• 负责人: Nia Bryant
• 金额: $ 42.34万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FE024904%2F1
• 关键词: Role; Sec1p; Munc18; SM; protein

All eukaryotic cells (ranging from yeast to humans) contain numerous compartments, each surrounded by a lipid membrane. This compartmentalisation provides the basis for intracellular specialisation. For example, in order to dispose of unwanted components cells have developed degradative enzymes; it is essential that these are sequestered away from other cellular components to avoid destruction of valuable molecules. In addition, the cell has developed a complex assembly line of modifications that are added to proteins in a specific order as they travel to their final destination within the cell. This necessitates the accurate passage of molecules between compartments: a process known as membrane trafficking. Small portions of membrane bud off from one compartment to form transport vesicles that carry molecules to another compartment. Fusion of the two membranes results in the delivery of the contents of the vesicle to the target compartment. It is essential that these transport vesicles fuse with the appropriate target membrane. This specificity is controlled by the formation of specific SNARE complexes between proteins in the donor (vesicle) and target membranes. SNARE complex formation also provides the energy required for the fusion of the two lipid bilayers. This proposal is directed towards understanding how the formation of these SNARE complexes is regulated, concentrating on the role of a family of proteins known as SM proteins. I hypothesise that SM proteins are carried by the v(esicle)-SNARE on the transport vesicle to the target membrane where they activate the t(arget)-SNARE, ready to form SNARE complexes and drive membrane fusion. The aim of this study is to test this hypothesis and elucidate the molecular mechanism(s) by which SM proteins control SNARE-mediated membrane fusion.

所有真核细胞（从酵母菌到人类）都含有大量的隔室，每个隔室都被脂质膜包围。这种区隔化为细胞内特化提供了基础。例如，为了处理不需要的成分，细胞产生了降解酶；至关重要的是，将这些物质与其他细胞成分隔离开来，以避免破坏有价值的分子。此外，细胞已经形成了一条复杂的修饰装配线，当蛋白质在细胞内到达最终目的地时，这些修饰以特定的顺序被添加到蛋白质中。这就需要分子在隔室之间准确地通过：这一过程被称为膜运输。膜的一小部分从一个腔室脱落，形成运输囊泡，将分子运送到另一个腔室。两个膜的融合导致囊泡的内容物递送到目标室。这些运输囊泡与适当的靶膜融合是至关重要的。这种特异性是由供体（囊泡）和靶膜中蛋白质之间形成的特异性SNARE复合物控制的。SNARE复合物的形成也为两个脂质双分子层的融合提供了所需的能量。这一建议旨在了解这些SNARE复合物的形成是如何被调节的，重点关注被称为SM蛋白的蛋白质家族的作用。我假设SM蛋白由运输囊泡上的v（囊泡）-SNARE携带到靶膜，在那里它们激活t（靶泡）-SNARE，准备形成SNARE复合物并驱动膜融合。本研究的目的是验证这一假设，并阐明SM蛋白控制snare介导的膜融合的分子机制。

项目成果

mVps45 knockdown selectively modulates VAMP expression in 3T3-L1 adipocytes.

• DOI: 10.1080/19420889.2015.1026494
• 发表时间: 2015-05
• 期刊: Communicative & integrative biology
• 作者: Sadler JB;Roccisana J;Virolainen M;Bryant NJ;Gould GW
• 通讯作者: Gould GW

The Thr224Asn mutation in the VPS45 gene is associated with the congenital neutropenia and primary myelofibrosis of infancy.

VPS45 基因中的 Thr224Asn 突变与先天性中性粒细胞减少症和婴儿期原发性骨髓纤维化有关。

• DOI: 10.1182/blood-2012-12-475566
• 发表时间: 2013
• 期刊: Blood
• 影响因子: 20.3
• 作者: Stepensky P

Proximity Ligation Assay to Study the GLUT4 Membrane Trafficking Machinery.

用于研究 GLUT4 膜运输机制的邻近连接测定。

• DOI: 10.1007/978-1-4939-7507-5_16
• 发表时间: 2018
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Kioumourtzoglou D

The Sec1/Munc18 protein Vps45 regulates cellular levels of its SNARE binding partners Tlg2 and Snc2 in Saccharomyces cerevisiae.

SEC1/MUNC18蛋白VPS45调节其在酿酒酵母中的网状结合伴侣TLG2和SNC2的细胞水平。

• DOI: 10.1371/journal.pone.0049628
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Shanks SG;Carpp LN;Struthers MS;McCann RK;Bryant NJ
• 通讯作者: Bryant NJ

Functional homology of mammalian syntaxin 16 and yeast Tlg2p reveals a conserved regulatory mechanism.

哺乳动物突触融合蛋白 16 和酵母 Tlg2p 的功能同源性揭示了保守的调节机制。

• DOI: 10.1242/jcs.046441
• 发表时间: 2009
• 期刊: Journal of cell science
• 影响因子: 4
• 作者: Struthers,MarionS;Shanks,ScottG;MacDonald,Chris;Carpp,LindsayN;Drozdowska,AlicjaM;Kioumourtzoglou,Dimitrios;Furgason,MelonnieLM;Munson,Mary;Bryant,NiaJ
• 通讯作者: Bryant,NiaJ