Structure of the gene therapy vector, adeno-associated virus with its cell receptor, AAVR
Structure of the gene therapy vector, adeno-associated virus with its cell receptor, AAVR
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DOI：
10.7554/elife.44707
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发表时间：
2019-05-22
期刊：
影响因子：
7.7
通讯作者：
Chapman, Michael Stewart
中科院分区：
文献类型：
--
作者：
Meyer, Nancy L.;Hu, Guiqing;Chapman, Michael Stewart
腺相关病毒(AAV)载体在新兴的临床基因治疗中具有优势。超越最易治疗的遗传性疾病的推广将需要调节细胞特异性和免疫中和。AAV与其细胞受体AAVR的相互作用是理解细胞进入和运输以及设计组织特异性载体所需的严谨所需的关键。冷冻电子断层扫描显示，部分柔性受体与病毒表面有序结合，远端结构域具有多种构象。物理上接近的病毒和受体的区域可以通过交联/质谱学来识别。带有两个结构域的受体片段的冷冻电子显微镜显示了2.4埃分辨率的相互作用。AAVR结合在AAV的尖峰之间，这是保守的，但在一个GLADE中，其结构与AAVR不相容。AAVR的足迹与几种中和抗体的表位重叠，促使对中和机制的重新评估。该结构为实验探测和操纵病毒-受体相互作用提供了路线图。
Adeno-associated virus (AAV) vectors are preeminent in emerging clinical gene therapies. Generalizing beyond the most tractable genetic diseases will require modulation of cell specificity and immune neutralization. Interactions of AAV with its cellular receptor, AAVR, are key to understanding cell-entry and trafficking with the rigor needed to engineer tissue-specific vectors. Cryo-electron tomography shows ordered binding of part of the flexible receptor to the viral surface, with distal domains in multiple conformations. Regions of the virus and receptor in close physical proximity can be identified by cross-linking/mass spectrometry. Cryo-electron microscopy with a two-domain receptor fragment reveals the interactions at 2.4 angstrom resolution. AAVR binds between AAV's spikes on a plateau that is conserved, except in one Glade whose structure is AAVR-incompatible. AAVR's footprint overlaps the epitopes of several neutralizing antibodies, prompting a re-evaluation of neutralization mechanisms. The structure provides a roadmap for experimental probing and manipulation of viral-receptor interactions.