The Assembly-Activating Protein Promotes Stability and Interactions between AAV's Viral Proteins to Nucleate Capsid Assembly
The Assembly-Activating Protein Promotes Stability and Interactions between AAV's Viral Proteins to Nucleate Capsid Assembly
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DOI：
10.1016/j.celrep.2018.04.026
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发表时间：
2018-05-08
期刊：
影响因子：
8.8
通讯作者：
Vandenberghe, Luk H.
中科院分区：
文献类型：
--
作者：
Maurer, Anna C.;Pacouret, Simon;Vandenberghe, Luk H.
腺相关病毒（AAV）载体是用于体内基因治疗的优选递送平台。AAV衣壳的天然和工程化变异影响与基因治疗相关的多种表型，包括载体产生和宿主向性。这些方面的基础是AAV衣壳组装的机制。在此，在12种天然存在的AAV和9种推定的祖先衣壳中间体中评价了病毒辅因子组装激活蛋白（AAP）的作用。结果表明在AAP存在下增加的衣壳蛋白稳定性和VP-VP相互作用。衣壳对AAP的依赖性可以通过加强组装体内单体之间的相互作用来部分克服，如通过转移由表型至基因组映射方法定义的最小基序所示。这些发现表明，依赖病毒属内AAP的出现放松了对AAV组装的结构约束，有利于增加衣壳进化的自由度。
The adeno-associated virus (AAV) vector is a preferred delivery platform for in vivo gene therapy. Natural and engineered variations of the AAV capsid affect a plurality of phenotypes relevant to gene therapy, including vector production and host tropism. Fundamental to these aspects is the mechanism of AAV capsid assembly. Here, the role of the viral cofactor assembly-activating protein (AAP) was evaluated in 12 naturally occurring AAVs and 9 putative ancestral capsid intermediates. The results demonstrate increased capsid protein stability and VP-VP interactions in the presence of AAP. The capsid's dependence on AAP can be partly overcome by strengthening interactions between monomers within the assembly, as illustrated by the transfer of a minimal motif defined by a phenotype-to-phylogeny mapping method. These findings suggest that the emergence of AAP within the Dependovirus genus relaxes structural constraints on AAV assembly in favor of increasing the degrees of freedom for the capsid to evolve.