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Tyrosine cross-linking reveals interfacial dynamics in adeno-associated viral capsids during infection

Academic Article
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Overview

authors

  • Horowitz, E. D.
  • Finn, M.G.
  • Asokan, A.

publication date

  • June 2012

journal

  • ACS Chemical Biology  Journal

abstract

  • Viral capsid dynamics are often observed during infectious events such as cell surface attachment, entry and genome release. Structural analysis of adeno-associated virus (AAV), a helper-dependent parvovirus, revealed a cluster of surface-exposed tyrosine residues at the icosahedral two-fold symmetry axis. We exploited the latter observation to carry out selective oxidation of Tyr residues, which yielded cross-linked viral protein (VP) subunit dimers, effectively "stitching" together the AAV capsid two-fold interface. Characterization of different Tyr-to-Phe mutants confirmed that the formation of cross-linked VP dimers is mediated by dityrosine adducts and requires the Tyr704 residue, which crosses over from one neighboring VP subunit to the other. When compared to unmodified capsids, Tyr-cross-linked AAV displayed decreased transduction efficiency in cell culture. Surprisingly, further biochemical and quantitative microscopy studies revealed that restraining the two-fold interface hinders externalization of buried VP N-termini, which contain a phospholipase A2 domain and nuclear localization sequences critical for infection. These adverse effects caused by tyrosine oxidation support the notion that interfacial dynamics at the AAV capsid two-fold symmetry axis play a role in externalization of VP N-termini during infection.

subject areas

  • Capsid
  • Capsid Proteins
  • Dependovirus
  • HEK293 Cells
  • HeLa Cells
  • Host-Pathogen Interactions
  • Humans
  • Models, Molecular
  • Mutation
  • Oxidation-Reduction
  • Parvoviridae Infections
  • Protein Multimerization
  • Protein Structure, Tertiary
  • Tyrosine
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Identity

PubMed Central ID

  • PMC3376196

International Standard Serial Number (ISSN)

  • 1554-8929

Digital Object Identifier (DOI)

  • 10.1021/cb3000265

PubMed ID

  • 22458529
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Additional Document Info

start page

  • 1059

end page

  • 1066

volume

  • 7

issue

  • 6

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