Adeno-associated virus-2 and its primary cellular receptor-Cryo-EM structure of a heparin complex

Jason O'Donnell, Kenneth A. Taylor, Michael S. Chapman

Research output: Contribution to journalArticle

75 Scopus citations

Abstract

Adeno-associated virus serotype 2 (AAV-2) is a leading candidate vector for gene therapy. Cell entry starts with attachment to a primary receptor, Heparan Sulfate Proteoglycan (HSPG) before binding to a co-receptor. Here, cryo-electron microscopy provides direct visualization of the virus-HSPG interactions. Single particle analysis was performed on AAV-2 complexed with a 17 kDa heparin fragment at 8.3 Å resolution. Heparin density covers the shoulder of spikes surrounding viral 3-fold symmetry axes. Previously implicated, positively charged residues R448/585, R451/588 and R350/487 from another subunit cluster at the center of the heparin footprint. The footprint is much more extensive than apparent through mutagenesis, including R347/484, K395/532 and K390/527 that are more conserved, but whose roles have been controversial. It also includes much of a region proposed as a co-receptor site, because prior studies had not revealed heparin interactions. Heparin density bridges over the viral 3-fold axes, indicating multi-valent attachment to symmetry-related binding sites.

Original languageEnglish (US)
Pages (from-to)434-443
Number of pages10
JournalVirology
Volume385
Issue number2
DOIs
StatePublished - Mar 15 2009

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Keywords

  • Electron microscopy
  • Gene therapy
  • Heparan sulfate
  • Heparin
  • Parvovirus

ASJC Scopus subject areas

  • Virology

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