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Cryo-EM Structure of Adeno-associated virus-4 at 2.2 Å resolution

View ORCID ProfileGrant M. Zane, Mark A. Silveria, View ORCID ProfileNancy L. Meyer, View ORCID ProfileTommi A. White, View ORCID ProfileMichael S. Chapman
doi: https://doi.org/10.1101/2022.01.12.476110
Grant M. Zane
1Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA
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Mark A. Silveria
1Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA
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Nancy L. Meyer
2Pacific Northwest Cryo-EM Center, Oregon Health Sciences University, Portland, OR 97201, USA
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Tommi A. White
1Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA
3Electron Microscopy Core, University of Missouri, Columbia, MO 65211, USA
4Bayer Crop Science, Bayer Crop Science, Chesterfield, MO 63017 USA
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Michael S. Chapman
1Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA
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  • For correspondence: chapmanms@missouri.edu
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Abstract

Adeno-associated virus (AAV) is the vector of choice for several approved gene therapy treatments and is the basis for many ongoing clinical trials. Various strains of AAV exist (referred to as serotypes), each with their own transfection characteristics. Here, we present a high-resolution cryo-electron microscopy structure (2.2 Å) for AAV serotype 4 (AAV4). The receptor responsible for transduction of the AAV4 clade of AAV viruses (including AAV11, 12 and rh32.33) is unknown. Other AAVs interact with the same cell receptor, Adeno-associated virus receptor (AAVR), in one of two different ways. AAV5-like viruses interact exclusively with the polycystic kidney disease-like [PKD]-1 domain of AAVR while most other AAVs interact primarily with the PKD2 domain. A comparison of the present AAV4 structure with prior corresponding structures of AAV5, AAV2 and AAV1 in complex with AAVR, provides a foundation for understanding why the AAV4-like clade is unable to interact with either PKD1 or PKD2. The conformation of the AAV4 capsid in variable regions I, III, IV and V on the viral surface appears to be sufficiently different from AAV2 to ablate binding with PKD2. Differences between AAV4 and AAV5 in variable region VII appear sufficient to exclude binding with PKD1.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted January 13, 2022.
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Cryo-EM Structure of Adeno-associated virus-4 at 2.2 Å resolution
Grant M. Zane, Mark A. Silveria, Nancy L. Meyer, Tommi A. White, Michael S. Chapman
bioRxiv 2022.01.12.476110; doi: https://doi.org/10.1101/2022.01.12.476110
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Cryo-EM Structure of Adeno-associated virus-4 at 2.2 Å resolution
Grant M. Zane, Mark A. Silveria, Nancy L. Meyer, Tommi A. White, Michael S. Chapman
bioRxiv 2022.01.12.476110; doi: https://doi.org/10.1101/2022.01.12.476110

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