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Journal of Virology, April 2004, p. 3361-3371, Vol. 78, No. 7
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.7.3361-3371.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Structure of Adeno-Associated Virus Serotype 5

Robert W. Walters,1,2,{dagger} Mavis Agbandje-McKenna,3,{dagger} Valorie D. Bowman,4,{dagger} Thomas O. Moninger,1 Norman H. Olson,4 Michael Seiler,1 John A. Chiorini,5 Timothy S. Baker,4 and Joseph Zabner1*

Departments of Internal Medicine,1 Physiology and Biophysics, College of Medicine, University of Iowa, Iowa City, Iowa 52242,2 Department of Biochemistry and Molecular Biology, Center for Structural Biology, The Brain Institute, University of Florida College of Medicine, Gainesville, Florida 32610,3 Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47907,4 Gene Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 208925

Received 2 September 2003/ Accepted 4 December 2003

Adeno-associated virus serotype 5 (AAV5) requires sialic acid on host cells to bind and infect. Other parvoviruses, including Aleutian mink disease parvovirus (ADV), canine parvovirus (CPV), minute virus of mice, and bovine parvovirus, also bind sialic acid. Hence, structural homology may explain this functional homology. The amino acids required for CPV sialic acid binding map to a site at the icosahedral twofold axes of the capsid. In contrast to AAV5, AAV2 does not bind sialic acid, but rather binds heparan sulfate proteoglycans at its threefold axes of symmetry. To explore the structure-function relationships among parvoviruses with respect to cell receptor attachment, we determined the structure of AAV5 by cryo-electron microscopy (cryo-EM) and image reconstruction at a resolution of 16 Å. Surface features common to some parvoviruses, namely depressions encircling the fivefold axes and protrusions at or surrounding the threefold axes, are preserved in the AAV5 capsid. However, even though there were some similarities, a comparison of the AAV5 structure with those of ADV and CPV failed to reveal a feature which could account for the sialic acid binding phenotype common to all three viruses. In contrast, the overall surface topologies of AAV5 and AAV2 are similar. A pseudo-atomic model generated for AAV5 based on the crystal structure of AAV2 and constrained by the AAV5 cryo-EM envelope revealed differences only in surface loop regions. Surprisingly, the surface topologies of AAV5 and AAV2 are remarkably similar to that of ADV despite only exhibiting ~20% identity in amino acid sequences. Thus, capsid surface features are shared among parvoviruses and may not be unique to their replication phenotypes, i.e., whether they require a helper or are autonomous. Furthermore, specific surface features alone do not explain the variability in carbohydrate requirements for host cell receptor interactions among parvoviruses.

* Corresponding author. Mailing address: University of Iowa College of Medicine, 500 EMRB, Iowa City, IA 52242. Phone: (319) 353-5511. Fax: (319) 335-7623. E-mail: joseph-zabner{at}uiowa.edu.

{dagger} R.W.W., M.A.-M., and V.D.B. contributed equally to this work.

Journal of Virology, April 2004, p. 3361-3371, Vol. 78, No. 7
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.7.3361-3371.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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