Crystal Structure of Human Herpesvirus 6B Tegument Protein U14.
Crystal Structure of Human Herpesvirus 6B Tegument Protein U14.
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DOI：
10.1371/journal.ppat.1005594
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发表时间：
2016-05
期刊：
影响因子：
6.7
通讯作者：
Mori Y
中科院分区：
文献类型：
--
作者：
Wang B;Nishimura M;Tang H;Kawabata A;Mahmoud NF;Khanlari Z;Hamada D;Tsuruta H;Mori Y
人类疱疹病毒6B(HHV-6B)的被膜蛋白U14构成病毒的病毒粒子结构，是病毒生长所必需的。为了确定U14的特性和功能，我们测定了HHV-6B U14(U14-NTD)的N-末端结构域的晶体结构，分辨率为1.85？U14-NTD形成一个细长的富含螺旋的折叠，带有一个突出的β发夹。U14-NTD以二聚体的形式存在，表现出广泛的静电相互作用和氢键网络。这是首次报道HHV-6B U14的晶体结构和二聚化反应。U14-NTD二聚体的表面显示多个带正负电荷的残基簇，这些残基与U14的潜在功能位点相吻合。与病毒生长有关的三个连续残基L424、E425和V426位于β发夹上，靠近二聚体的双重轴。L424和V426的疏水侧链构成了疏水斑块的一部分，它们在溶剂中暴露，表明β发夹区域可能是HHV-6U14的关键功能位点。基于结构的序列比较表明，U14-NTD对应于U14同源物、人类疱疹病毒7U14和人巨细胞病毒UL25和UL35之间保守的核心折叠，尽管二聚化似乎是U14组的一个特有特征。人类疱疹病毒6B(HHV-6B)是一种儿童和免疫功能低下的成人皮疹的病原体，它编码许多组成病毒基质的被蛋白。HHV-6B U14是病毒繁殖所必需的被膜蛋白，此外，它还与宿主因子如肿瘤抑制因子P53和细胞蛋白EDD相互作用，从而调节宿主细胞的反应。在这里，我们报道了HHV-6B U14在原子分辨率下的分子结构。U14(U14-NTD)的N-末端结构域采用了一个拉长的富含螺旋的折叠，与已知结构没有任何显著的总体相似性。U14-NTD通过静电相互作用和广泛的氢键网络形成100 kDa的均二聚体。U14-NTD同源二聚体显示四个具有深凹槽的静电势簇，这意味着其他病毒或宿主蛋白有多个结合位点。U14-NTD对应于人类疱疹病毒7型(HHV-7)和人巨细胞病毒(CMV)的同源蛋白共享的核心折叠，尽管二聚化似乎是HHV-6和HHV-7所特有的。U14-NTD结构为进一步分析U14在HHV-6致病机制中的作用和行为提供了线索。它还有助于全面了解贝塔疱疹病毒中的U14同源物，并进一步有助于全面了解疱疹病毒中的被膜蛋白。
The tegument protein U14 of human herpesvirus 6B (HHV-6B) constitutes the viral virion structure and is essential for viral growth. To define the characteristics and functions of U14, we determined the crystal structure of the N-terminal domain of HHV-6B U14 (U14-NTD) at 1.85 Å resolution. U14-NTD forms an elongated helix-rich fold with a protruding β hairpin. U14-NTD exists as a dimer exhibiting broad electrostatic interactions and a network of hydrogen bonds. This is first report of the crystal structure and dimerization of HHV-6B U14. The surface of the U14-NTD dimer reveals multiple clusters of negatively- and positively-charged residues that coincide with potential functional sites of U14. Three successive residues, L424, E425 and V426, which relate to viral growth, reside on the β hairpin close to the dimer's two-fold axis. The hydrophobic side-chains of L424 and V426 that constitute a part of a hydrophobic patch are solvent-exposed, indicating the possibility that the β hairpin region is a key functional site of HHV-6 U14. Structure-based sequence comparison suggests that U14-NTD corresponds to the core fold conserved among U14 homologs, human herpesvirus 7 U14, and human cytomegalovirus UL25 and UL35, although dimerization appears to be a specific feature of the U14 group. Human herpesvirus 6B (HHV-6B), a causative agent of exanthema subitum for children and immunocompromised adults, encodes numerous tegument proteins that constitute the viral matrix. HHV-6B U14 is a tegument protein essential for viral propagation, and additionally it interacts with host factors such as tumor suppressor p53 and cellular protein EDD, thereby regulating host cell responses. Here, we report the molecular structure of HHV-6B U14 at an atomic resolution. The N-terminal domain of U14 (U14-NTD) adopts an elongated, helix-rich fold without any significant overall similarity to known structures. U14-NTD forms a 100 kDa homodimer through electrostatic interactions and a wide hydrogen bond network. The U14-NTD homodimer displays four clusters of electrostatic potential with deep grooves, implying multiple binding sites for other viral or host proteins. U14-NTD corresponds to the core fold shared by homologous proteins of human herpesvirus 7 (HHV-7) and of human cytomegalovirus, although dimerization seems to be specific to HHV-6 and HHV-7. The U14-NTD structure provides clues to promote further analysis on the role and behavior of U14 in the pathogenesis of HHV-6. It also leads to a comprehensive understanding of the U14 homologs in beta herpesviruses, and furthermore contributes to the overall knowledge about tegument proteins in herpesviruses.