Structure of the membrane anchor of pestivirus glycoprotein E(rns), a long tilted amphipathic helix.
Structure of the membrane anchor of pestivirus glycoprotein E(rns), a long tilted amphipathic helix.
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DOI：
10.1371/journal.ppat.1003973
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发表时间：
2014-02
期刊：
影响因子：
6.7
通讯作者：
Meyers G
中科院分区：
文献类型：
--
作者：
Aberle D;Muhle-Goll C;Bürck J;Wolf M;Reißer S;Luy B;Wenzel W;Ulrich AS;Meyers G
Erns是一种重要的病毒粒子糖蛋白，具有rna酶活性，从感染细胞中部分分泌，可抑制宿主细胞的先天免疫反应。其独特的c端起着多种作用，两亲性螺旋作为膜锚，作为信号肽酶裂解位点，并作为保留/分泌信号。我们分析了该序列的结构和膜结合特性，以更好地了解其潜在机制。不同设置下的CD光谱，以及蒙特卡罗和分子动力学模拟证实了螺旋折叠，并表明螺旋被安置在脂质双分子层的两亲性区域，并有轻微的倾斜，而不是平行于表面。核磁共振分析也证实了这一模型，该模型还确定了螺旋内部有15个残基的中心延伸，完全屏蔽了水层，这是c端，然后是一个假定的发夹结构。这些发现解释了该蛋白的强膜结合，并为建立Erns膜接触、加工和分泌提供了线索。鼠疫病毒的Erns蛋白（包膜蛋白，RNase，分泌）是病毒学中最令人着迷的蛋白质之一。Erns不仅是病毒颗粒的基本结构成分，也是一种非特异性rna酶。后一种活性对于鼠疫病毒的复制是必不可少的，但它代表了一个毒力因素，涉及建立终身持续感染。Erns的这些功能与其对感染宿主I型干扰素反应的抑制活性有关，这可能取决于感染细胞内合成的部分蛋白的分泌，然后随血流分布。为了了解导致细胞内保留（用于产生病毒颗粒）和分泌（用于抑制先天免疫反应）之间平衡的机制，需要更好地了解Erns膜结合的原理。然而，最近发表的Erns晶体结构缺乏相关的羧基末端膜锚区。我们在此报告了与模型膜结合的Erns膜锚的结构分析。这项工作基于圆二色性、核磁共振波谱和结构模拟，揭示了一种新型的表面蛋白膜锚。这些数据将有助于解释厄恩的不寻常功能。
Erns is an essential virion glycoprotein with RNase activity that suppresses host cellular innate immune responses upon being partially secreted from the infected cells. Its unusual C-terminus plays multiple roles, as the amphiphilic helix acts as a membrane anchor, as a signal peptidase cleavage site, and as a retention/secretion signal. We analyzed the structure and membrane binding properties of this sequence to gain a better understanding of the underlying mechanisms. CD spectroscopy in different setups, as well as Monte Carlo and molecular dynamics simulations confirmed the helical folding and showed that the helix is accommodated in the amphiphilic region of the lipid bilayer with a slight tilt rather than lying parallel to the surface. This model was confirmed by NMR analyses that also identified a central stretch of 15 residues within the helix that is fully shielded from the aqueous layer, which is C-terminally followed by a putative hairpin structure. These findings explain the strong membrane binding of the protein and provide clues to establishing the Erns membrane contact, processing and secretion. The Erns protein (envelope protein, RNase, secreted) of pestiviruses represents one of the most fascinating proteins in virology. Erns is not only an essential structural component of the virus particle but also an unspecific RNase. The latter activity is dispensable for pestivirus replication but represents a virulence factor involved in the establishment of lifelong persistent infection. These functions of Erns are connected with its repressive activity on the type I interferon response of the infected host probably depending on secretion of part of the protein synthesized within the infected cell followed by its distribution with the blood stream. To understand the mechanisms leading to an equilibrium between intracellular retention (for production of virus particles) and secretion (for repression of the innate immune response) the principles of Erns membrane binding need to be better understood. The recently published Erns crystal structure, however, is lacking the relevant carboxyterminal membrane anchor region. We report here structure analyses of the Erns membrane anchor bound to model membranes. This work was based on circular dichroism, nuclear magnetic resonance spectroscopy, and structure simulations, and revealed a new type of membrane anchor for a surface protein. These data will help to explain the unusual functions of Erns.
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