Cryo-EM structure of adeno-associated virus 4 at 2.2 Å resolution

Zane, Grant; Silveria, Mark; Meyer, Nancy; White, Tommi; Duan, Rui; Zou, Xiaoqin; Chapman, Michael

doi:10.1107/s2059798322012190

Cryo-EM structure of adeno-associated virus 4 at 2.2 Å resolution

Journal Article · Fri Jan 20 00:00:00 EST 2023 · Acta Crystallographica. Section D. Structural Biology

DOI:https://doi.org/10.1107/s2059798322012190· OSTI ID:2424147

Zane, Grant ^[1]; Silveria, Mark ^[1]; Meyer, Nancy ^[2]; White, Tommi ^[3]; Duan, Rui ^[1]; Zou, Xiaoqin ^[1]; Chapman, Michael ^[1]

Univ. of Missouri, Columbia, MO (United States)
Oregon Health Sciences University, Portland, OR (United States)
Univ. of Missouri, Columbia, MO (United States); Bayer Crop Science, Chesterfield, MO (United States)

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, a high-resolution cryo-electron microscopy structure (2.2 Å) of AAV serotype 4 (AAV4) is presented. The receptor responsible for transduction of the AAV4 clade of AAV viruses (including AAV11, AAV12 and AAVrh32.33) 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 1 (PKD1) 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 of AAVR. 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 to be sufficient to exclude binding with PKD1.

View Accepted Manuscript (DOE)

Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States). Environmental Molecular Sciences Laboratory (EMSL)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 2424147

Journal Information:: Acta Crystallographica. Section D. Structural Biology, Journal Name: Acta Crystallographica. Section D. Structural Biology Journal Issue: 2 Vol. 79; ISSN 2059-7983

Publisher:: International Union of CrystallographyCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
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cryo-electron microscopy
gene therapy

Cryo-EM structure of adeno-associated virus 4 at 2.2 Å resolution

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