Cited by 219Virus-based gene therapy researchParvovirus B19 Infection StudiesRNA Interference and Gene Delivery

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Structural Insight into the Unique Properties of Adeno-Associated Virus Serotype 9

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DiMattia, Michael A., Nam, Hyun-Joo, Van Vliet, Kim, Mitchell, Matthew, Bennett, Antonette, Gurda, Brittney L., McKenna, Robert, Olson, Norman H., Sinkovits, Robert S., Potter, Mark, Byrne, Barry J., Aslanidi, George, Zolotukhin, Sergei, Muzyczka, Nicholas, Baker, Timothy S., Agbandje-McKenna, Mavis·2012·Journal of Virology

DOI 10.1128/jvi.07232-11PMC PMC3393551

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Abstract

Adeno-associated virus serotype 9 (AAV9) has enhanced capsid-associated tropism for cardiac muscle and the ability to cross the blood-brain barrier compared to other AAV serotypes. To help identify the structural features facilitating these properties, we have used cryo-electron microscopy (cryo-EM) and three-dimensional image reconstruction (cryo-reconstruction) and X-ray crystallography to determine the structure of the AAV9 capsid at 9.7- and 2.8-Å resolutions, respectively. The AAV9 capsid exhibits the surface topology conserved in all AAVs: depressions at each icosahedral two-fold symmetry axis and surrounding each five-fold axis, three separate protrusions surrounding each three-fold axis, and a channel at each five-fold axis. The AAV9 viral protein (VP) has a conserved core structure, consisting of an eight-stranded, β-barrel motif and the αA helix, which are present in all parvovirus structures. The AAV9 VP differs in nine variable surface regions (VR-I to -IX) compared to AAV4, but at only three (VR-I, VR-II, and VR-IV) compared to AAV2 and AAV8. VR-I differences modify the raised region of the capsid surface between the two-fold and five-fold depressions. The VR-IV difference produces smaller three-fold protrusions in AAV9 that are less “pointed” than AAV2 and AAV8. Significantly, residues in the AAV9 VRs have been identified as important determinants of cellular tropism and transduction and dictate its antigenic diversity from AAV2. Hence, the AAV9 VRs likely confer the unique infection phenotypes of this serotype.

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Authors: DiMattia, M. A., Nam, H.-J., Van Vliet, K., Mitchell, M., Bennett, A., Gurda, B. L., McKenna, R., Olson, N. H., Sinkovits, R. S., Potter, M., Byrne, B. J., Aslanidi, G., Zolotukhin, S., Muzyczka, N., Baker, T. S., & Agbandje-McKenna, M.
Affiliations: University of Florida (US)
Department of Biochemistry and Molecular Biology, Center for Structural Biology, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, Florida, USA
University of California San Diego (US)
University of Florida Health (US)
ORCID: DiMattia, Michael A.
Bennett, Antonette
Gurda, Brittney L.
McKenna, Robert
Sinkovits, Robert S.
Potter, Mark
Byrne, Barry J.
Aslanidi, George
Baker, Timothy S.
Venue: Journal of Virology
Publisher: American Society for Microbiology
Published: 2012-06-15
Volume: 86
Issue: 12
Pages: 6947-6958
ISSN: 0022-538X (ISSN-L)
1098-5514
DOI: 10.1128/jvi.07232-11
PMC: PMC3393551
OpenAlex: W2012799865
Cited by: 219
References: 91
Citations by year: 2026: 15 · 2025: 18 · 2024: 17 · 2023: 16 · 2022: 26 · 2021: 23 · 2020: 18 · 2019: 16 · 2018: 15 · 2017: 6 · 2016: 11 · 2015: 9 · 2014: 12 · 2013: 11 · 2012: 4
FWCI: 6.94
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Journal of Virology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
eScholarship (California Digital Library) (submittedVersion)
Funders: National Science Foundation
National Institutes of Health (4r37gm033050-27)
University of California, San Francisco
National Heart, Lung, and Blood Institute (P01HL059412, P01 HL 59412)
National Institute of General Medical Sciences (R37GM-033050, R37 GM-33050, DMR-0225180, R01GM082946)
Division of Materials Research
National Center for Research Resources (RR-01646, S10RR020016, P41RR001646, P41RR001081)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
Health Sciences › Medicine › Infectious Diseases › Parvovirus B19 Infection Studies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Keywords: AAV9, viral tropism, blood-brain barrier penetration, antigenic diversity, 3D reconstruction
MeSH terms: Dependovirus, Capsid, Crystallography, X-Ray, Cryoelectron Microscopy, Imaging, Three-Dimensional, Capsid Proteins

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Structural Insight into the Unique Properties of Adeno-Associated Virus Serotype 9

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