Bibliographic Details
| Title: |
Structural basis of the recognition of adeno-associated virus by the neurological system-related receptor carbonic anhydrase IV. |
| Authors: |
Zhang, Ran1,2 (AUTHOR), Liu, Yixiao2 (AUTHOR), Yu, Fengxi3 (AUTHOR), Xu, Guangxue4 (AUTHOR), Li, Lili5 (AUTHOR), Li, Baobin6 (AUTHOR), Lou, Zhiyong2 (AUTHOR) louzy@mail.tsinghua.edu.cn |
| Superior Title: |
PLoS Pathogens. 2/5/2024, Vol. 20 Issue 2, p1-20. 20p. |
| Subject Terms: |
*CARBONIC anhydrase, *ADENO-associated virus, *CENTRAL nervous system, *BLOOD-brain barrier, *ADENOVIRUSES, CENTRAL nervous system infections |
| Abstract: |
Carbonic anhydrase IV (Car4) is a newly identified receptor that allows adeno-associated virus (AAV) 9P31 to cross the blood-brain barrier and achieve efficient infection in the central nervous system (CNS) in mouse models. However, the molecular mechanism by which engineered AAV capsids with 7-mer insertion in the variable region (VR) VIII recognize these novel cellular receptors is unknown. Here we report the cryo-EM structures of AAV9P31 and its complex with Mus musculus Car4 at atomic resolution by utilizing the block-based reconstruction (BBR) method. The structures demonstrated that Car4 binds to the protrusions at 3-fold axes of the capsid. The inserted 7-mer extends into a hydrophobic region near the catalytic center of Car4 to form stable interactions. Mutagenesis studies also identified the key residues in Car4 responsible for the AAV9P31 interaction. These findings provide new insights into the novel receptor recognition mechanism of AAV generated by directed evolution and highlight the application of the BBR method to studying the virus-receptor molecular mechanism. Author summary: Recombinant adeno-associated viruses (AAVs) are promising vectors for gene therapy, especially for metabolic, neurological and hematological diseases. Among them, AAV9P31, which was designed based on the AAV9 backbone, is a highly effective candidate for gene delivery in the central nervous system. To optimize this vector, it is crucial to understand how AAV9P31 recognizes its receptor carbonic anhydrase IV (Car4) and crosses the blood-brain barrier. In this study, we determined the atomic structures of AAV9P31 in its native state and in complex with Car4, revealing the molecular details of virus-receptor interactions. Moreover, we applied the block-based reconstruction algorithm to capture the asymmetric binding of the receptor on the icosahedral virus, which is important for studying recombinant AAV targeting neurological receptors. [ABSTRACT FROM AUTHOR] |
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