Conformational Changes in Adeno-Associated Virus Type 1 Induced by Genome Packaging

Britta Gerlach, Juergen A. Kleinschmidt, Bettina Boettcher

Research output: Contribution to journalArticlepeer-review

Abstract

Adeno-associated virus (AAV) is frequently used as a vector for gene therapy. The viral capsid consists of three structural proteins (VP1, VP2, and VP3) that have a common C-terminal core (VP3), with N-terminal extensions of increasing length in VP2 and VP1. The capsid encloses a single-stranded genome of up to 4.7 kb, which is packaged into empty capsids. The N-terminal extension of VP1 carries a phospholipase domain that becomes accessible during infection in the endosomal pathway. We have used cryo-electron microscopy and image reconstruction to determine subnanometer-resolution structures of recombinant AAV1 that has packaged different amounts of a 3. 6-kb recombinant genome. The maps show that the AAV1 capsid undergoes continuous conformational changes upon packaging of the genome. The rearrangements occur at the inner capsid surface and lead to constrictions of the pores at the 5-fold symmetry axes and to subtle movements of the beta-sheet regions of the capsid proteins. In fully packaged particles, the genome forms stem-like features that contact the inner capsid surface at the 3-fold symmetry axes. We think that the reorganization of the inner surface has an impact on the viral life cycle during infection, preparing the externalization of phospholipase domains through the pores at the 5-fold symmetry axes and possibly genome release.

Original languageEnglish
Pages (from-to)427-438
Number of pages12
JournalJournal of Molecular Biology
Volume409
Issue number3
Early online date2 Apr 2011
DOIs
Publication statusPublished - 10 Jun 2011

Keywords

  • AAV1
  • DNA packaging
  • conformational changes
  • cryo-electron microscopy
  • icosahedral image reconstruction

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