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Heparin binding induces conformational changes in Adeno-associated virus serotype 2
Open accessAbstract
Adeno-associated virus serotype 2 (AAV2) uses heparan sulfate proteoglycan as a cell surface-attachment receptor. In this study the structures of AAV2 alone and complexed with heparin were determined to approximately 18A resolution using cryo-electron microscopy and three-dimensional image reconstruction. A difference map showed positive density, modeled as heparin, close to the icosahedral twofold axes and between the protrusions that surround the threefold axes of the capsid. Regions of the model near the threefold place the receptor in close proximity to basic residues previously identified as part of the heparin binding site. The region of the model near the twofold axes identifies a second contact site, not previously characterized but which is also possibly configured by heparin binding. The difference map also revealed two significant conformational changes: (I) at the tops of the threefold protrusions, which have become flattened in the complex, and (II) at the fivefold axes where the top of the channel is widened possibly in response to movement of the HI loops in the capsid proteins. Ordered density in the interior of the capsid in the AAV2-heparin complex was interpreted as nucleic acid, consistent with the presence of non-viral DNA in the expressed capsids.
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“For example, for AAV2, two critical residues required for binding HS, R585 and R588, reside within VR-VIII, and the 511-NGR-513 proposed to play a role in α5β1 co-receptor binding is flanked by VR-I and VR-IV (Asokan et al., 2006; Kern et al., 2003; Levy et al., 2009; Ng et al., 2010; Opie et al., 2003; Shen et al., 2015; Summerford and Samulski, 1998).”
From Structure comparison of the chimeric AAV2.7m8 vector with parental AAV2 (2020) · cites this paper as Levy et al., 2009
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“different types of contaminating DNA sequences have been described as being copackaged with the transgenes, including fragments of the host cell genome from the cells that are used during vector production [81].”
From Understanding Capsid Assembly and Genome Packaging for Adeno-Associated Viruses (2017) · cites this paper as [81]
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“It has been demonstrated previously that empty particles may contain small fragments of genomic material, 50 but the contents were unknown.”
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“The previous reports thus support reports of AAV packaging cellular pieces of DNA in the absence of Rep proteins (59).”
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“Belief in large-scale glycan-induced conformational change persisted due to hints thereof in an independently determined structure of an AAV2-heparin complex at 18 Å resolution [162].”
BackgroundPénzes, J. J., Chipman, P. R., Bhattacharya, N., Zeher, A., Huang, R. K., McKENNA, R. V., & Agbandje‐McKenna, M. (2021) · Journal of Virology · doi:10.1128/jvi.00843-21 · Cited by 55
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“Both studies stand in stark contrast to the inference of large induced changes from subtle differences in maps of AAV-2 at much lower (18Å) resolution (Levy et al., 2009).”
ResultTunable Protease-Activatable Virus Nanonodes
Judd, J., Ho, M. L., Tiwari, A., Gomez, E. J., Dempsey, C., Vliet, K. V., Igoshin, O. A., Silberg, J. J., Agbandje‐McKenna, M., & Suh, J. (2014) · ACS Nano · doi:10.1021/nn500550q · Cited by 54
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“The HI loop, which forms interactions between icosahedral five-fold symmetry related VPs and lies on the floor of the depression surrounding this axis, was also proposed to undergo a conformational re-arrangement that opens up the channel located at the icosahedral fivefold axis following heparin binding by AAV2 [41].”
BackgroundSelf-citationCryo-electron Microscopy of Adeno-associated Virus
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“Specifically, AAV2, AAV3, AAV6, and AAV13 use residues located in VR-V, VR-VI, and VR-VIII to bind HSPG.(30,36,37).”
BackgroundInfluentialSelf-citationStructures and Functions of Parvovirus Capsids and the Process of Cell Infection
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“HSPG binding is associated with surface-exposed patches of positively charged residues, and binding induces small changes in the capsid structure, which are detectable by cryoEM analysis (Levy et al. 2009; O’Donnell et al. 2009) (Fig.”
BackgroundThe structure of AAVrh32.33, a novel gene delivery vector
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Peptide ligands for the affinity purification of adeno‐associated viruses from HEK 293 cell lysates
Chu, W., Shastry, S., Barbieri, E., Prodromou, R., Greback‐Clarke, P., Smith, W. K., Moore, B., Kilgore, R., Cummings, C., Pancorbo, J., et al. (2023) · Biotechnology and Bioengineering · doi:10.1002/bit.28495 · Cited by 33
“…capsid proteins VP1 (~87 kDa), VP2 (~73 kDa), and VP3 (~62 kDa) in the correct ~1:1:10 ratio (DiMattia et al., 2012; Drouin & Agbandje‐McKenna, 2013; Levy et al., 2009) based on the densitometric analysis of the gels, corroborating our interpretative hypothesis that only fully formed capsids are…”
BackgroundArnett, A. L. H., Beutler, L. R., Quintana, A., Allen, J. M., Finn, E. E., Palmiter, R. D., & Chamberlain, J. S. (2012) · Gene Therapy · doi:10.1038/gt.2012.60 · Cited by 34
Structure comparison of the chimeric AAV2.7m8 vector with parental AAV2
Bennett, A., Keravala, A., Makal, V., Kurian, J., Belbellaa, B., Aeran, R., Tseng, Y.-S., Sousa, D., Spear, J., Gasmi, M., et al. (2020) · Journal of Structural Biology · doi:10.1016/j.jsb.2019.107433 · Cited by 33
“For example, for AAV2, two critical residues required for binding HS, R585 and R588, reside within VR-VIII, and the 511-NGR-513 proposed to play a role in α5β1 co-receptor binding is flanked by VR-I and VR-IV (Asokan et al., 2006; Kern et al., 2003; Levy et al., 2009; Ng et al., 2010; Opie et al., 2003; Shen et al., 2…”
BackgroundInfluentialSelf-citationZeng, C., Møller-Tank, S., Asokan, A., & Dragnea, B. G. (2017) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.6b10131 · Cited by 33
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“Given the dependency of AAV2 on HSPG for subsequent steps in cell transduction, such as priming the capsid for co-receptor binding, endosomal escape, and uncoating, 32 it is reasonable to postulate that the low HSPG expression level negatively impacts AAV2 transduction efficiency.”
Barbash, I. M., Cecchini, S., Faranesh, A. Z., Virág, T., Li, L., Yang, Y., Hoyt, R. F., Kornegay, J. N., Bogan, J. R., Garcı́a, L., et al. (2012) · Gene Therapy · doi:10.1038/gt.2012.38 · Cited by 32
Functional Analysis of the Putative Integrin Recognition Motif on Adeno-associated Virus 9
Shen, S., Berry, G. E., Rivera, R. M. C., Cheung, R., Troupes, A. N., Brown, S. M., Kafri, T., & Asokan, A. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.608281 · Cited by 26
Choijilsuren, G., Jhou, R., Chou, S.-F., Chang, C.-J., Yang, H., Chen, Y.-Y., Chuang, W., Yu, M., & Shih, C. (2017) · Scientific Reports · doi:10.1038/s41598-017-14573-9 · Cited by 27
Atomic Resolution Structures of Human Bufaviruses Determined by Cryo-Electron Microscopy
Ilyas, M., Mietzsch, M., Kailasan, S., Väisänen, E., Luo, M., Chipman, P. R., Smith, J. K., Kurian, J. J., Sousa, D. R., McKENNA, R. V., et al. (2018) · Viruses · doi:10.3390/v10010022 · Cited by 25
Self-citationConformational Changes in Adeno-Associated Virus Type 1 Induced by Genome Packaging
Gerlach, B., Kleinschmidt, J. A., & Böttcher, B. (2011) · Journal of Molecular Biology · doi:10.1016/j.jmb.2011.03.062 · Cited by 24
Adeno‐associated virus serotype 2 capsid variants for improved liver‐directed gene therapy
Meumann, N., Cabanes‐Creus, M., Ertelt, M., Navarro, R. G., Lucifora, J., Yuan, Q., Nien‐Huber, K., Abdelrahman, A. M., Vu, X., Zhang, L. N., et al. (2022) · Hepatology · doi:10.1002/hep.32733 · Cited by 26
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Exploiting Natural Diversity of AAV for the Design of Vectors with Novel Properties
Gao, G., Li, Z., & Danos, O. (2011) · Methods in molecular biology · doi:10.1007/978-1-61779-370-7_4 · Cited by 24
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Bioengineered Viral Platform for Intramuscular Passive Vaccine Delivery to Human Skeletal Muscle
Paulk, N. K., Pekrun, K., Charville, G. W., Maguire, K., Wosczyna, M. N., Xu, J., Zhang, Y., Lisowski, L., Yoo, B., Vilches-Moure, J. G., et al. (2018) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2018.06.001 · Cited by 19
Multiparametric domain insertional profiling of adeno-associated virus VP1
Hoffmann, M. D., Zdechlik, A. C., He, Y., Nedrud, D. M., Aslanidi, G., Gordon, W. R., & Schmidt, D. (2023) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2023.101143 · Cited by 18
Structural Insight into Non-Enveloped Virus Binding to Glycosaminoglycan Receptors: A Review
Sorin, M. N., Kuhn, J., Stasiak, A. C., & Stehle, T. (2021) · Viruses · doi:10.3390/v13050800 · Cited by 17
“Among the first structures of AAV–GAG complexes are two examples that were solved before the cryoEM “resolution revolution” [17], at lower resolutions of 18 Å [18] and 8 Å [19].”
BackgroundStructural characterization of a bat Adeno-associated virus capsid
Mietzsch, M., Li, Y., Kurian, J. J., Smith, J. K., Chipman, P. R., McKENNA, R. V., Yang, L., & Agbandje‐McKenna, M. (2020) · Journal of Structural Biology · doi:10.1016/j.jsb.2020.107547 · Cited by 17
Self-citationXie, Q., Spilman, M. S., Meyer, N., Lerch, T. F., Stagg, S. M., & Chapman, M. S. (2013) · Journal of Structural Biology · doi:10.1016/j.jsb.2013.09.004 · Cited by 17
Macdonald, J., Marx, J., & Büning, H. (2021) · Human Gene Therapy · doi:10.1089/hum.2021.169 · Cited by 17
“26 The VRs mentioned earlier are primarily found at capsid protrusions, which represent sites of interactions between AAVs and the host cell and define receptor binding and immunogenicity.”
Ye, X., Hu, Y., Qiu, H., & Li, N. (2024) · Protein Science · doi:10.1002/pro.5074 · Cited by 15
Zhang, Y., Chen, Z., Wang, X., Yan, R., Bao, H., Chu, X., Guo, L., Wang, X., Li, Y., Mu, Y., et al. (2024) · Acta Biomaterialia · doi:10.1016/j.actbio.2024.07.023 · Cited by 13
Research Progress on Antiviral Activity of Heparin
Wang, Y., Zhang, Y., Wang, P., Jing, T., Hu, Y., & Chen, X. (2023) · Current Medicinal Chemistry · doi:10.2174/0929867330666230203124032 · Cited by 10
The amazing AAV capsids: Into the structure-verse
Hsi, J., Mietzsch, M., & McKENNA, R. V. (2025) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2025.101629 · Cited by 9
“146 Similarly, a synthetic heparinoid was complexed with the engineered AAV-DJ capsid (see the capsid structures of engineered AAVs section) by cryo-EM at 2.8 Å resolution, showing density for the glycan at the apices of the 3-fold protrusions.”
InfluentialSelf-citationUse of a Lower Dosage Liver-Detargeted AAV Vector to Prevent Hamster Muscular Dystrophy
Rotundo, I. L., Lancioni, A., Savarese, M., D’Orsi, L., Iacomino, M., Nigro, G., Piluso, G., Auricchio, A., & Nigro, V. (2013) · Human Gene Therapy · doi:10.1089/hum.2012.121 · Cited by 6
“424 residue 520 or residues 560–590, corresponding to the heparan sulfate (HS) binding site (Hileman et al., 1998; Summerford and Samulski, 1998; Wu et al., 2000; Shi et al., 2001; Levy et al., 2009) that acts as a primary receptor.”
BackgroundThe Role of Carbohydrates in Viral Infections
Air, G. M. (2011) · Wiley eBooks · doi:10.1002/9781118017586.ch3 · Cited by 7
Adeno-associated Virus as a Mammalian DNA Vector
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Biologics-device combinations: Enabling prolonged therapies in the posterior segment ocular disease
Zhu, S., Zhang, J., Jiang, X., Peng, C., Liu, H., & Qian, F. (2026) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2026.115773 · Cited by 3
Viral Vectors for Gene Delivery
Dismuke, D. J., Gray, S. J., Hirsch, M. L., Samulski, R. J., & Muzyczka, N. (2010) · Royal Society of Chemistry eBooks · doi:10.1039/9781849732239-00338 · Cited by 3
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“…vectors with wild-type capsids, interactions with extracellular matrix components, such as heparan sulfate proteoglycan (HSPG) for AAV2, initiate cell transduction and facilitate binding to coreceptors, 32 promoting the internalization process, for example, through clathrin-dependent endocytosis.”
Cui, M., Liu, H., Cai, L., Zhang, Q., Yuan, L., Gao, C., Li, C., Xi, J., Li, Y., Wu, C., et al. (2026) · Molecular Therapy Advances · doi:10.1016/j.omta.2026.201806 · Cited by 1
“32,44 The investigation into the mechanisms underlying the enhanced transduction profile of AAV2.”
Nonenveloped Capsid: Mechanisms of Viral Entry
Lins, B., & Agbandje‐McKenna, M. (2014) · Future Virology · doi:10.2217/fvl.14.82 · Cited by 1
Self-citationImmune System Obstacles to In vivo Gene Transfer with Adeno-Associated Virus Vectors
Büning, H., & Mingozzi, F. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-800563-7.00004-x · Cited by 1
UNDERSTANDING THE SOLUTION-PHASE BIOPHYSICS AND CONFORMATIONAL DYNAMICS OF VIRUS CAPSIDS
Rayaprolu, V. (2013) · Montana State University ScholarWorks (Montana State University)
Metadata
- Authors
- Levy, H. C., Bowman, V. D., Govindasamy, L., McKenna, R., Nash, K., Warrington, K., Chen, W., Muzyczka, N., Yan, X., Baker, T. S., & Agbandje-McKenna, M.
- Affiliations
- University of Florida (US)
- Purdue University West Lafayette (US)
- University of California San Diego (US)
- Venue
- Journal of Structural Biology
- Publisher
- Elsevier BV
- Published
- 2009-03
- Volume
- 165
- Issue
- 3
- Pages
- 146-156
- ISSN
- 1047-8477 (ISSN-L)
- PMC
- PMC3694330
- OpenAlex
- W2156683693
- Cited by
- 110
- References
- 76
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 8 · 2020: 3 · 2019: 10 · 2018: 2 · 2017: 5 · 2016: 7 · 2015: 8 · 2014: 10 · 2013: 11 · 2012: 10
- FWCI
- 4.13
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Journal of Structural Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (4r37gm033050-27)
- National Heart, Lung, and Blood Institute (P01HL059412, P01HL051811)
- National Institute of General Medical Sciences (R37GM-033050)
- National Institute of Allergy and Infectious Diseases (P01AI045976)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Advanced Electron Microscopy Techniques and Applications
- Keywords
- AAV2, heparin binding, capsid conformational change, heparan sulfate proteoglycans, capsid structure
- MeSH terms
- Dependovirus, Capsid, Heparin, Image Processing, Computer-Assisted, Models, Molecular, Protein Conformation, Virion, Mutagenesis, Site-Directed, Nucleocapsid, Cryoelectron Microscopy, Capsid Proteins
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