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TitleStructural basis of the recognition of adeno-associated virus by the neurological system-related receptor carbonic anhydrase IV.
Journal, issue, pagesPLoS Pathog, Vol. 20, Issue 2, Page e1011953, Year 2024
Publish dateFeb 5, 2024
AuthorsRan Zhang / Yixiao Liu / Fengxi Yu / Guangxue Xu / Lili Li / Baobin Li / Zhiyong Lou /
PubMed AbstractCarbonic 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 ...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.
External linksPLoS Pathog / PubMed:38315719 / PubMed Central
MethodsEM (single particle)
Resolution1.76 - 2.28 Å
Structure data

36311

8jif

EMDB-36311, PDB-8jif:
Cryo-EM Structure of 3-axis block of AAV9P31-Car4 complex
Method: EM (single particle) / Resolution: 2.28 Å

38289

8xeg

EMDB-38289, PDB-8xeg:
Cryo-EM structure of Adeno-associated Virus 9P31 in 1.76 angstrom.
Method: EM (single particle) / Resolution: 1.76 Å

EMDB-38672: Icosahedral Reconstructed map of Car4-bound state AAV9P31 at 1.76 Angstroms
Method: EM (single particle) / Resolution: 1.76 Å

Chemicals

ChemComp-ZN:
Unknown entry

Source
  • mus musculus (house mouse)
  • adeno-associated virus 9
KeywordsVIRAL PROTEIN/LYASE / receptor / aav9p31 / Carbonic anhydrases iv / Block-based reconstruction / VIRUS / VIRAL PROTEIN-LYASE complex / Dependo parvovirus

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