The structure of adeno-associated virus serotype 3B (AAV-3B): Insights into receptor binding and immune evasion

Lerch, Thomas F.; Xie, Qing; Chapman, Michael S.

doi:10.1016/j.virol.2010.03.027

Cited by 88 publications

(115 citation statements)

References 60 publications

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“…The refinement and molecular geometry statistics are consistent with those reported for other members of the Parvoviridae as well as structures determined for other virus families at comparable resolution, as reported on the VIPERdb website (http://viperdb.scripps.edu/). As has been previously reported for other AAV capsid structures, the Nterminal region of VP2 and the first 15 amino acids of VP3 were unresolved in both the cryo-EM and X-ray structures (23,36,37,47,52,66,73). In all of these AAV structures, only the overlapping C-terminal VP (ϳ520-aa) region common to the VP1, VP2, and VP3 sequence is unambiguously resolved.…”

Section: Resultssupporting

confidence: 69%

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Structural Characterization of the Dual Glycan Binding Adeno-Associated Virus Serotype 6

Govindasamy

Gurda

et al. 2010

J Virol

122

137

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The three-dimensional structure of adeno-associated virus (AAV) serotype 6 (AAV6) was determined using cryo-electron microscopy and image reconstruction and using X-ray crystallography to 9.7-and 3.0-Å resolution, respectively. The AAV6 capsid contains a highly conserved, eight-stranded (␤B to ␤I) ␤-barrel core and large loop regions between the strands which form the capsid surface, as observed in other AAV structures. The loops show conformational variation compared to other AAVs, consistent with previous reports that amino acids in these loop regions are involved in differentiating AAV receptor binding, transduction efficiency, and antigenicity properties. Toward structure-function annotation of AAV6 with respect to its unique dual glycan receptor (heparan sulfate and sialic acid) utilization for cellular recognition, and its enhanced lung epithelial transduction compared to other AAVs, the capsid structure was compared to that of AAV1, which binds sialic acid and differs from AAV6 in only 6 out of 736 amino acids. Five of these residues are located at or close to the icosahedral 3-fold axis of the capsid, thereby identifying this region as imparting important functions, such as receptor attachment and transduction phenotype. Two of the five observed amino acids are located in the capsid interior, suggesting that differential AAV infection properties are also controlled by postentry intracellular events. Density ordered inside the capsid, under the 3-fold axis in a previously reported, conserved AAV DNA binding pocket, was modeled as a nucleotide and a base, further implicating this capsid region in AAV genome recognition and/or stabilization.

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Section: Resultssupporting

confidence: 69%

“…A total of nine variable regions (VRs; VRI to VRIX) were defined when the two most disparate structures, AAV2 and AAV4, were compared (23). The VRs contain amino acids that contribute to slight differences in surface topologies and distinct functional phenotypes, such as in receptor binding, transduction efficiency, and antigenic reactivity (10,23,37,47).…”

mentioning

confidence: 99%

Structural Characterization of the Dual Glycan Binding Adeno-Associated Virus Serotype 6

Govindasamy

Gurda

et al. 2010

J Virol

122

137

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“…Unlike the structures determined for some other AAV capsids, for example, AAV3B, AAV4, AAV6, and AAV8, including VLPs produced in baculovirus/Sf9 expression systems (e.g., AAV6 and AAV8), where at least one DNA nucleotide is ordered (22,23,26,27,29), there was no DNA ordered in the AAV5 capsid interior in the previously identified DNA binding pocket, despite the conservation of the binding pocket amino acids. The lack of ordering of a nucleotide in AAV5 is predicted to be due to the high radiation sensitivity of the thin crystals used for X-ray diffraction data collection.…”

Section: Resultsmentioning

confidence: 57%

“…An additional visual comparison of the superposition of the structures was carried out using the Coot program (62). The available crystal structures of AAV3b, AAV6, AAV8, and AAV9 (23,26,27,29) were not included in this analysis due to their high similarity to AAV2 and the fact that regions which vary between them and AAV2 were already described when this serotype was compared to AAV4.…”

Section: Methodsmentioning

confidence: 99%

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Structural Insights into Adeno-Associated Virus Serotype 5

Govindasamy

DiMattia

Gurda

et al. 2013

J Virol

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The adeno-associated viruses (AAVs) display differential cell binding, transduction, and antigenic characteristics specified by their capsid viral protein (VP) composition. Toward structure-function annotation, the crystal structure of AAV5, one of the most sequence diverse AAV serotypes, was determined to 3.45-Å resolution. The AAV5 VP and capsid conserve topological features previously described for other AAVs but uniquely differ in the surface-exposed HI loop between ␤H and ␤I of the core ␤-barrel motif and have pronounced conformational differences in two of the AAV surface variable regions (VRs), VR-IV and VR-VII. The HI loop is structurally conserved in other AAVs despite amino acid differences but is smaller in AAV5 due to an amino acid deletion. This HI loop is adjacent to VR-VII, which is largest in AAV5. The VR-IV, which forms the larger outermost finger-like loop contributing to the protrusions surrounding the icosahedral 3-fold axes of the AAVs, is shorter in AAV5, creating a smoother capsid surface topology. The HI loop plays a role in AAV capsid assembly and genome packaging, and VR-IV and VR-VII are associated with transduction and antigenic differences, respectively, between the AAVs. A comparison of interior capsid surface charge and volume of AAV5 to AAV2 and AAV4 showed a higher propensity of acidic residues but similar volumes, consistent with comparable DNA packaging capacities. This structure provided a three-dimensional (3D) template for functional annotation of the AAV5 capsid with respect to regions that confer assembly efficiency, dictate cellular transduction phenotypes, and control antigenicity. R ecombinant adeno-associated viruses (rAAVs) are promising viral vectors for gene delivery applications (1, 2). These viruses belong to the single-stranded DNA (ssDNA)-packaging Parvoviridae and genus Dependovirus. Hundreds of AAV genotypes have been sequenced from several mammalian species, and to date 12 serotypes (AAV1 to AAV12) have been defined for the human and nonhuman primate isolates (3-15). The 12 serotypes are classified into eight genetic groups, clades A to F and clonal isolates AAV4 and AAV5, based on antigenic reactivity and sequence similarity (15). The groups are represented by AAV1 to AAV9, with AAV1 and AAV6 belonging to the same clade A because of their high sequence similarity and antigenic cross-reactivity. The representative members share ϳ55 to 99% sequence identity, with AAV4 and AAV5 being the most divergent from each other and from the other members.The linear ssDNA AAV genome, ϳ4.7 kb in length, contains two genes: cap, which encodes the capsid viral proteins (VPs; VP1, ϳ87 kDa; VP2, ϳ73 kDa; VP3, ϳ62 kDa) and rep, which encodes the replication proteins necessary for genome replication and genome packaging. Inverted terminal repeats (ITRs) at the end of the AAV genome, 145 bp in length, are the only essential active sequence required to function as (i) the origin for DNA replication, (ii) the packaging signal, and (iii) integration sites (16)(17)(18)(19). Recombina...

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High‐Resolution Imaging of Human Viruses in Liquid Droplets

et al. 2021

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Liquid‐phase electron microscopy (LP‐EM) is an exciting new area in the materials imaging field, providing unprecedented views of molecular processes. Time‐resolved insights from LP‐EM studies are a strong complement to the remarkable results achievable with other high‐resolution techniques. Here, the opportunities to expand LP‐EM technology beyond 2D temporal assessments and into the 3D regime are described. The results show new structures and dynamic insights of human viruses contained in minute volumes of liquid while acquired in a rapid timeframe. To develop this strategy, adeno‐associated virus (AAV) is used as a model system. AAV is a well‐known gene therapy vehicle with current applications involving drug delivery and vaccine development for COVID‐19. Improving the understanding of the physical properties of biological entities in a liquid state, as maintained in the human body, has broad societal implications for human health and disease.

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The structure of adeno-associated virus serotype 3B (AAV-3B): Insights into receptor binding and immune evasion

Cited by 88 publications

References 60 publications

Structural Characterization of the Dual Glycan Binding Adeno-Associated Virus Serotype 6

Structural Characterization of the Dual Glycan Binding Adeno-Associated Virus Serotype 6

Structural Insights into Adeno-Associated Virus Serotype 5

High‐Resolution Imaging of Human Viruses in Liquid Droplets

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