MOE Laboratory of Protein Science and Collaborative Innovation Center of Biotherapy, School of Medicine, Tsinghua University, Beijing, China.
School of Life Sciences, Tsinghua University, Beijing, China.
Nat Microbiol. 2019 Apr;4(4):675-682. doi: 10.1038/s41564-018-0356-7. Epub 2019 Feb 11.
Adeno-associated virus (AAV) is a leading vector for virus-based gene therapy. The receptor for AAV (AAVR; also named KIAA0319L) was recently identified, and the precise characterization of AAV-AAVR recognition is in immediate demand. Taking advantage of a particle-filtering algorithm, we report here the cryo-electron microscopy structure of the AAV2-AAVR complex at 2.8 Å resolution. This structure reveals that of the five Ig-like polycystic kidney disease (PKD) domains in AAVR, PKD2 binds directly to the spike region of the AAV2 capsid adjacent to the icosahedral three-fold axis. Residues in strands B and E, and the BC loop of AAVR PKD2 interact directly with the AAV2 capsid. The interacting residues in the AAV2 capsid are mainly in AAV-featured variable regions. Mutagenesis of the amino acids at the AAV2-AAVR interface reduces binding activity and viral infectivity. Our findings provide insights into the biology of AAV entry with high-resolution details, providing opportunities for the development of new AAV vectors for gene therapy.
腺相关病毒（AAV）是病毒为基础的基因治疗的主要载体。AAV 的受体（AAVR；也称为 KIAA0319L）最近被鉴定出来，因此对 AAV-AAVR 识别的精确特征化有直接的需求。利用粒子滤波算法，我们在这里报道了 2.8Å 分辨率的 AAV2-AAVR 复合物的冷冻电子显微镜结构。该结构揭示了 AAVR 中的五个 Ig 样多囊肾病（PKD）结构域中，PKD2 直接与位于二十面体三重轴附近的 AAV2 衣壳的刺突区域结合。AAVR PKD2 的 B 链和 E 链以及 BC 环中的残基直接与 AAV2 衣壳相互作用。AAV2 衣壳中的相互作用残基主要位于 AAV 特征性的可变区。AAV2-AAVR 界面处氨基酸的突变会降低结合活性和病毒感染力。我们的发现提供了具有高分辨率细节的 AAV 进入生物学的见解，为基因治疗的新型 AAV 载体的开发提供了机会。
