Analysis of localization, topology, membrane binding, secretion and function of the pestivirus structural glacoprotein Erns

瘟病毒结构糖蛋白 Erns 的定位、拓扑、膜结合、分泌和功能分析

基本信息

项目摘要

Pestiviruses belong to the family Flaviviridae and produce enveloped virions with a single stranded RNA genome of positive polarity. They have established fascinating mechanisms for establishment of long lasting persistence and are of major importance for veterinary medicine (Lindenbach et al, 2007).Pestivirus particles contain glycoprotein Erns that represents a crucial factor for virulence and persistence of pestivirus. It possesses RNase activity (Hulst & Moormann, 2001; Hulst et al, 1998; Schneider et al, 1993; Windisch et al, 1996), which we identified as virulence factor and cofactor for establishment of persistence (Meyer et al, 2002; Meyers et al, 1999; Tews et al, 2009; Meyers et al, 2007). Erns contains no typical membrane anchor and is partially secreted from infected cells (Magkouras et al, 2008; Mätzener et al, 2009; Rümenapf et al, 1993) whereas the overwhelming amount of the synthesized protein remains membrane bound within the ER or an ER-related compartment (Burrack et al, 2012; Tews & Meyers, 2007; Tews et al, 2009). The carboxyterminal region of Erns represents an unusual membrane anchor dar (Tews & Meyers, 2007; Tews et al, 2009), ensures the intracellular localization of the protein, the biologically important homodimerization and the processing of the Erns/E1 precursor. We could recently show that the Erns membrane anchor folds into an amphipathic helix in contact with a membrane. Unexpectedly the central part of this helix is located within the lipid bilayer. It contains a series of charged residues that could form a so-called charge zipper motif (Walther et al, 2013). The mechanism of Erns membrane anchoring and the function of the charge zipper motif in membrane anchoring will be analyzed with molecular techniques. Further structure analysis of the membrane bound anchor will be conducted in cooperation. The virulence factor function of Erns is dependent on the RNase activity and homodimer formation. We have isolated from animals a pseudorevertant that regained the ability to form dimers by a mutation in the middle of the membrane anchor. This finding raises questions concerning the primary sequence requirements and timely coordination of dimer formation, Erns/E1 processing and initiation of membrane binding, which will be investigated during the coming grant period. Erns secretion is hypothesized to be curcial for ist function as a virulence factor. We aim to analyze how the equilibrium between specific intracellular localization and secretion of the protein is achieved. Moreover, the role of the charge zipper motif for the insertion of the Erns carboxyterminus into the membrane and the influence of other viral proteins on Erns retention and recruitment into the virus particle will be investigated.
瘟病毒属于黄病毒科并且产生具有正极性的单链RNA基因组的包膜病毒体。它们已经建立了建立持久持久性的迷人机制,并且对于兽医学具有重要意义(Lindenbach等人,2007)Jestivirus颗粒含有糖蛋白Erns,其代表了瘟病毒的毒力和持久性的关键因素。它具有RNA酶活性(胡尔斯特& Moormann,2001;胡尔斯特et al,1998; Schneider et al,1993;温迪施et al,1996),我们将其鉴定为用于建立持久性的毒力因子和辅因子(Meyer et al,2002; Meyers et al,1999; Tews et al,2009; Meyers et al,2007)。Erns不含典型的膜锚,部分从感染细胞分泌(Magkouras et al,2008; Mätzener et al,2009; Rümenapf et al,1993),而绝大多数合成蛋白质仍与ER或ER相关区室膜结合(Burrack et al,2012; Tews & Meyers,2007; Tews et al,2009)。Erns的羧基末端区域代表不寻常的膜锚区(Tews & Meyers,2007; Tews等人,2009),确保蛋白质的细胞内定位、生物学上重要的同源二聚化和Erns/E1前体的加工。我们最近可以证明,厄恩斯膜锚折叠成一个两亲性螺旋接触膜。出乎意料的是,该螺旋的中心部分位于脂质双层内。它含有一系列带电残基,可形成所谓的电荷拉链基序(Walther et al,2013)。利用分子技术分析Erns膜锚定的机制以及电荷拉链基序在膜锚定中的作用。将配合进行膜约束锚的进一步结构分析。Erns的毒力因子功能依赖于RNase活性和同源二聚体的形成。我们已经从动物中分离出一种假回复突变体,它通过在膜锚中间的突变恢复了形成二聚体的能力。这一发现提出了有关的主要序列的要求和及时协调的二聚体形成,Erns/E1处理和启动膜结合,这将是在未来的补助期间进行调查的问题。Erns分泌被认为是一种特异性的毒力因子。我们的目的是分析如何实现特定的细胞内定位和分泌的蛋白质之间的平衡。此外,电荷拉链基序的作用,Erns羧基末端插入到膜和其他病毒蛋白对Erns保留和招募到病毒颗粒的影响将进行研究。

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A new type of intracellular retention signal identified in a pestivirus structural glycoprotein
  • DOI:
    10.1096/fj.12-207191
  • 发表时间:
    2012-08-01
  • 期刊:
  • 影响因子:
    4.8
  • 作者:
    Burrack, Sandra;Aberle, Daniel;Meyers, Gregor
  • 通讯作者:
    Meyers, Gregor
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Professor Dr. Gregor Meyers其他文献

Professor Dr. Gregor Meyers的其他文献

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{{ truncateString('Professor Dr. Gregor Meyers', 18)}}的其他基金

Characterization of the molecular features of the pestivirus Erns protein with regard to ist function as structural component of the virion and virulence factor
瘟病毒 Erns 蛋白作为病毒粒子和毒力因子结构成分的功能的分子特征表征
  • 批准号:
    313902382
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Mechanismen der Genexpression bei Caliciviren
杯状病毒基因表达机制
  • 批准号:
    5349798
  • 财政年份:
    2002
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Entstehung zytopathogener Pestiviren durch RNA Rekombination/Mutation - molekulare Ursachen der Zytopathogenität und Verbindung zu einer tödlichen Krankheit
通过 RNA 重组/突变出现细胞致病性瘟病毒 - 细胞致病性的分子原因以及与致命疾病的联系
  • 批准号:
    5230556
  • 财政年份:
    1997
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Molekulare Charakterisierung des Calicivirus "Rabbit Hemorrhagic Disease Virus" (RHDV) und "Felines Calicivirus" (FCV)
杯状病毒“兔出血性疾病病毒”(RHDV) 和“猫杯状病毒”(FCV) 的分子特征
  • 批准号:
    5181569
  • 财政年份:
    1995
  • 资助金额:
    --
  • 项目类别:
    Research Grants

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