Structural Insights into Adeno-Associated Virus Serotype 5
Structural Insights into Adeno-Associated Virus Serotype 5
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DOI：
10.1128/jvi.00867-13
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发表时间：
2013-10-01
影响因子：
5.4
通讯作者：
Agbandje-McKenna, Mavis
中科院分区：
文献类型：
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作者：
Govindasamy, Lakshmanan;DiMattia, Michael A.;Agbandje-McKenna, Mavis
腺相关病毒（AAV）显示由其衣壳病毒蛋白（VP）组成所指定的差异细胞结合、转导和抗原特性。对于结构-功能注释，AAV 5（最序列多样性的AAV血清型之一）的晶体结构被确定为3.45埃分辨率。AAV 5 VP和衣壳保留先前针对其他AAV描述的拓扑特征，但在核心β-桶基序的β H和β I之间的表面暴露的Hl环中独特地不同，并且在两个AAV表面可变区（VR）VR-IV和VR-VII中具有显著的构象差异。Hl环在其他AAV中结构保守，尽管存在氨基酸差异，但由于氨基酸缺失，Hl环在AAV 5中较小。该HI环与VR-VII相邻，VR-VII在AAV 5中最大。VR-IV，其形成较大的最外指状环，有助于围绕AAV的二十面体3重轴的突起，在AAV 5中较短，产生更平滑的衣壳表面拓扑结构。HI环在AAV衣壳组装和基因组包装中起作用，并且VR-IV和VR-VII分别与AAV之间的转导和抗原差异相关。AAV 5与AAV 2和AAV 4的内部衣壳表面电荷和体积的比较显示酸性残基的更高倾向但相似的体积，与相当的DNA包装能力一致。该结构提供了三维（3D）模板，用于AAV 5衣壳相对于赋予组装效率、决定细胞转导表型和控制抗原性的区域的功能注释。
The adeno-associated viruses (AAVs) display differential cell binding, transduction, and antigenic characteristics specified by their capsid viral protein (VP) composition. Toward structure-function annotation, the crystal structure of AAV5, one of the most sequence diverse AAV serotypes, was determined to 3.45-angstrom resolution. The AAV5 VP and capsid conserve topological features previously described for other AAVs but uniquely differ in the surface-exposed HI loop between beta H and beta I of the core beta-barrel motif and have pronounced conformational differences in two of the AAV surface variable regions (VRs), VR-IV and VR-VII. The HI loop is structurally conserved in other AAVs despite amino acid differences but is smaller in AAV5 due to an amino acid deletion. This HI loop is adjacent to VR-VII, which is largest in AAV5. The VR-IV, which forms the larger outermost finger-like loop contributing to the protrusions surrounding the icosahedral 3-fold axes of the AAVs, is shorter in AAV5, creating a smoother capsid surface topology. The HI loop plays a role in AAV capsid assembly and genome packaging, and VR-IV and VR-VII are associated with transduction and antigenic differences, respectively, between the AAVs. A comparison of interior capsid surface charge and volume of AAV5 to AAV2 and AAV4 showed a higher propensity of acidic residues but similar volumes, consistent with comparable DNA packaging capacities. This structure provided a three-dimensional (3D) template for functional annotation of the AAV5 capsid with respect to regions that confer assembly efficiency, dictate cellular transduction phenotypes, and control antigenicity.