Structure-function analysis of receptor-binding in adeno-associated virus serotype 6 (AAV-6)

Qing Xie; Thomas F. Lerch; Nancy L. Meyer; Michael S. Chapman

doi:10.1016/j.virol.2011.08.011

Structure-function analysis of receptor-binding in adeno-associated virus serotype 6 (AAV-6)

Qing Xie
, Thomas F. Lerch
, Nancy L. Meyer
, Michael S. Chapman

Research output: Contribution to journal › Article › peer-review

64 Scopus citations

Abstract

Crystal structures of the AAV-6 capsid at 3Å reveal a subunit fold homologous to other parvoviruses with greatest differences in two external loops. The electrostatic potential suggests that receptor-attachment is mediated by four residues: Arg₅₇₆, Lys₄₉₃, Lys₄₅₉ and Lys₅₃₁, defining a positively charged region curving up from the valley between adjacent spikes. It overlaps only partially with the receptor-binding site of AAV-2, and the residues endowing the electrostatic character are not homologous. Mutational substitution of each residue decreases heparin affinity, particularly Lys₅₃₁ and Lys₄₅₉. Neither is conserved among heparin-binding serotypes, indicating that diverse modes of receptor attachment have been selected in different serotypes. Surface topology and charge are also distinct at the shoulder of the spike, where linear epitopes for AAV-2's neutralizing monoclonal antibody A20 come together. Evolutionarily, selection of changed side-chain charge may have offered a conservative means to evade immune neutralization while preserving other essential functionality.

Original language	English (US)
Pages (from-to)	10-19
Number of pages	10
Journal	Virology
Volume	420
Issue number	1
DOIs	https://doi.org/10.1016/j.virol.2011.08.011
State	Published - Nov 10 2011
Externally published	Yes

Funding

The authors would like to thank Heather M. Ongley, Thayumanasamy Somasundaram, Weishu Bu and the staff at CHESS who helped with data collection. Thanks are also due to Andrew Trzynka and Omar Davulcu for technical support. CHESS is supported by the NSF and NIH/NIGMS via NSF award DMR-0225180 , and the MacCHESS resource is supported by NIH/NCRR award RR-01646 . This research is supported by the National Institute of Health R01-GM66875 (M.S.C) and the American Heart Association 10-post-2600203 (TFL).

Funders	Funder number
NIH NCRR	RR-01646
NIH/NIGMS	DMR-0225180
National Institute of Health National Eye Institute	R01-GM66875
Author National Science Foundation National Science Foundation National Institutes of Health National Institutes of Health National Institutes of Health National Institutes of Health National Science Foundation National Science Foundation
National Center for Research Resources	P41RR001646
American Heart Association/American Stroke Association	10-post-2600203

Keywords

Antibody
Crystal
Gene therapy
Parvovirus
Receptor
Structure

ASJC Scopus subject areas

Virology

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10.1016/j.virol.2011.08.011

Cite this

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title = "Structure-function analysis of receptor-binding in adeno-associated virus serotype 6 (AAV-6)",

abstract = "Crystal structures of the AAV-6 capsid at 3{\AA} reveal a subunit fold homologous to other parvoviruses with greatest differences in two external loops. The electrostatic potential suggests that receptor-attachment is mediated by four residues: Arg576, Lys493, Lys459 and Lys531, defining a positively charged region curving up from the valley between adjacent spikes. It overlaps only partially with the receptor-binding site of AAV-2, and the residues endowing the electrostatic character are not homologous. Mutational substitution of each residue decreases heparin affinity, particularly Lys531 and Lys459. Neither is conserved among heparin-binding serotypes, indicating that diverse modes of receptor attachment have been selected in different serotypes. Surface topology and charge are also distinct at the shoulder of the spike, where linear epitopes for AAV-2's neutralizing monoclonal antibody A20 come together. Evolutionarily, selection of changed side-chain charge may have offered a conservative means to evade immune neutralization while preserving other essential functionality.",

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author = "Qing Xie and Lerch, \{Thomas F.\} and Meyer, \{Nancy L.\} and Chapman, \{Michael S.\}",

note = "Funding Information: The authors would like to thank Heather M. Ongley, Thayumanasamy Somasundaram, Weishu Bu and the staff at CHESS who helped with data collection. Thanks are also due to Andrew Trzynka and Omar Davulcu for technical support. CHESS is supported by the NSF and NIH/NIGMS via NSF award DMR-0225180 , and the MacCHESS resource is supported by NIH/NCRR award RR-01646 . This research is supported by the National Institute of Health R01-GM66875 (M.S.C) and the American Heart Association 10-post-2600203 (TFL). ",

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N2 - Crystal structures of the AAV-6 capsid at 3Å reveal a subunit fold homologous to other parvoviruses with greatest differences in two external loops. The electrostatic potential suggests that receptor-attachment is mediated by four residues: Arg576, Lys493, Lys459 and Lys531, defining a positively charged region curving up from the valley between adjacent spikes. It overlaps only partially with the receptor-binding site of AAV-2, and the residues endowing the electrostatic character are not homologous. Mutational substitution of each residue decreases heparin affinity, particularly Lys531 and Lys459. Neither is conserved among heparin-binding serotypes, indicating that diverse modes of receptor attachment have been selected in different serotypes. Surface topology and charge are also distinct at the shoulder of the spike, where linear epitopes for AAV-2's neutralizing monoclonal antibody A20 come together. Evolutionarily, selection of changed side-chain charge may have offered a conservative means to evade immune neutralization while preserving other essential functionality.

AB - Crystal structures of the AAV-6 capsid at 3Å reveal a subunit fold homologous to other parvoviruses with greatest differences in two external loops. The electrostatic potential suggests that receptor-attachment is mediated by four residues: Arg576, Lys493, Lys459 and Lys531, defining a positively charged region curving up from the valley between adjacent spikes. It overlaps only partially with the receptor-binding site of AAV-2, and the residues endowing the electrostatic character are not homologous. Mutational substitution of each residue decreases heparin affinity, particularly Lys531 and Lys459. Neither is conserved among heparin-binding serotypes, indicating that diverse modes of receptor attachment have been selected in different serotypes. Surface topology and charge are also distinct at the shoulder of the spike, where linear epitopes for AAV-2's neutralizing monoclonal antibody A20 come together. Evolutionarily, selection of changed side-chain charge may have offered a conservative means to evade immune neutralization while preserving other essential functionality.

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KW - Receptor

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Structure-function analysis of receptor-binding in adeno-associated virus serotype 6 (AAV-6)

Abstract

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Keywords

ASJC Scopus subject areas

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