Structure of the gene therapy vector, adeno-associated virus with its cell receptor, AAVR

  1. Nancy L Meyer
  2. Guiqing Hu
  3. Omar Davulcu
  4. Qing Xie
  5. Alex J Noble
  6. Craig Yoshioka
  7. Drew S Gingerich
  8. Andrew Trzynka
  9. Larry David
  10. Scott M Stagg
  11. Michael Stewart Chapman  Is a corresponding author
  1. Oregon Health and Science University, United States
  2. Florida State University, United States
  3. University of Missouri, United States

Abstract

Adeno-associated virus (AAV) vectors are preeminent in emerging clinical gene therapies. Generalizing beyond the most tractable genetic diseases will require modulation of cell specificity and immune neutralization. Interactions of AAV with its cellular receptor, AAVR, are key to understanding cell-entry and trafficking with the rigor needed to engineer tissue-specific vectors. Cryo-electron tomography shows ordered binding of part of the flexible receptor to the viral surface, with distal domains in multiple conformations. Regions of the virus and receptor in close physical proximity can be identified by cross-linking / mass spectrometry. Cryo-electron microscopy with a two-domain receptor fragment reveals the interactions at 2.4 Å resolution. AAVR binds between AAV's spikes on a plateau that is conserved, except in one clade whose structure is AAVR-incompatible. AAVR's footprint overlaps the epitopes of several neutralizing antibodies, prompting a re-evaluation of neutralization mechanisms. The structure provides a roadmap for experimental probing and manipulation of viral-receptor interactions.

Data availability

Electron microscopy maps and atomic coordinates will be available from the electron microscopy and protein data banks (https://www.ebi.ac.uk/pdbe/emdb/ & https://www.rcsb.org/). For the high resolution PKD1-2/AAV2 complex, the accession numbers are EMD-0553, PDB ID 6NZ0, respectively. Reconstructions for the 4 tomographic classes have accession numbers of EMD-0621, EMD-0622, EMD-0623 and EMD-0624.

The following data sets were generated

Article and author information

Author details

  1. Nancy L Meyer

    Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6836-6688
  2. Guiqing Hu

    Institute Molecular Biophysics, Florida State University, Tallahassee, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Omar Davulcu

    Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Qing Xie

    Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Alex J Noble

    Institute Molecular Biophysics, Florida State University, Tallahassee, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8634-2279
  6. Craig Yoshioka

    Center for Spatial Systems Biomedicine, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0251-7316
  7. Drew S Gingerich

    Center for Spatial Systems Biomedicine, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Andrew Trzynka

    Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Larry David

    Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Scott M Stagg

    Institute Molecular Biophysics, Florida State University, Tallahassee, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Michael Stewart Chapman

    Department of Biochemistry, University of Missouri, Columbia, United States
    For correspondence
    chapmanms@missouri.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8525-8585

Funding

National Institutes of Health (R35GM122564)

  • Andrew Trzynka

National Institutes of Health (R01GM066875)

  • Michael Stewart Chapman

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Sriram Subramaniam, University of British Columbia, Canada

Version history

  1. Received: December 24, 2018
  2. Accepted: May 22, 2019
  3. Accepted Manuscript published: May 22, 2019 (version 1)
  4. Version of Record published: June 12, 2019 (version 2)

Copyright

© 2019, Meyer et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Nancy L Meyer
  2. Guiqing Hu
  3. Omar Davulcu
  4. Qing Xie
  5. Alex J Noble
  6. Craig Yoshioka
  7. Drew S Gingerich
  8. Andrew Trzynka
  9. Larry David
  10. Scott M Stagg
  11. Michael Stewart Chapman
(2019)
Structure of the gene therapy vector, adeno-associated virus with its cell receptor, AAVR
eLife 8:e44707.
https://doi.org/10.7554/eLife.44707

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https://doi.org/10.7554/eLife.44707

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