Impact of VP1-Specific Protein Sequence Motifs on Adeno-Associated Virus Type 2 Intracellular Trafficking and Nuclear Entry
Open accessAbstract
Adeno-associated virus type 2 (AAV2) has gained much interest as a gene delivery vector. A hallmark of AAV2-mediated gene transfer is an intracellular conformational change of the virus capsid, leading to the exposure of infection-relevant protein domains. These protein domains, which are located on the N-terminal portion of the structural proteins VP1 and VP2, include a catalytic phospholipase A 2 domain and three clusters of basic amino acids. We have identified additional protein sequence motifs located on the VP1/2 N terminus that also proved to be obligatory for virus infectivity. These motifs include signals that are known to be involved in protein interaction, endosomal sorting and signal transduction in eukaryotic cells. Among different AAV serotypes they are highly conserved and mutation of critical amino acids of the respective motifs led to a severe infection-deficient phenotype. In particular, mutation of a YXXQ-sequence motif significantly reduced accumulation of virus capsids around the nucleus in comparison to wild-type AAV2. Interestingly, intracellular trafficking of AAV2 was shown to be independent of PLA 2 activity. Moreover, mutation of three PDZ-binding motifs, which are located consecutively at the very tip of the VP1 N terminus, revealed a nuclear transport-defective phenotype, suggesting a role in nuclear uptake of the virus through an as-yet-unknown mechanism.
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Residues located at the two- and fivefold interfaces of the VP, secondary structure elements, and close to the fivefold channel play a role in capsid assembly.
“Residues located at the two- and fivefold interfaces of the VP, secondary structure elements and close to the fivefold channel play a role in capsid assembly (Table 1 & Figure 4) [36–37].”
From Understanding Capsid Assembly and Genome Packaging for Adeno-Associated Viruses (2017) · cites this paper as [37]
Cites
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- Authors
- Popa-Wagner, R., Porwal, M., Kann, M., Reuss, M., Weimer, M., Florin, L., & Kleinschmidt, J. A.
- Affiliations
- German Cancer Research Center (DE)
- Justus-Liebig-Universität Gießen (DE)
- Laboratoire de Microbiologie Fondamentale et Pathogénicité (FR)
- Johannes Gutenberg University Mainz (DE)
- Venue
- Journal of Virology
- Publisher
- American Society for Microbiology
- Published
- 2012-09
- Volume
- 86
- Issue
- 17
- Pages
- 9163-9174
- ISSN
- 0022-538X (ISSN-L)
- 1098-5514
- PMC
- PMC3416132
- OpenAlex
- W2105017686
- Cited by
- 109
- References
- 13
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 12 · 2023: 12 · 2022: 8 · 2021: 8 · 2020: 4 · 2019: 13 · 2018: 6 · 2017: 7 · 2016: 5 · 2015: 8 · 2014: 3 · 2013: 8
- FWCI
- 3.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Virology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- adeno-associated virus type 2, VP1, VP2, nuclear entry, PDZ-binding motif, capsid conformational change, gene delivery vectors
- MeSH terms
- Dependovirus, Amino Acid Sequence, Cell Line, Cell Nucleus, Humans, Molecular Sequence Data, Parvoviridae Infections, Sequence Alignment, Amino Acid Motifs, Protein Transport, Capsid Proteins
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