Structure of the gene therapy vector, adeno-associated virus with its cell receptor, AAVR
- Oregon Health and Science University, United States
- Florida State University, United States
- 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.
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Cryo-EM structure of AAV-2 in complex with AAVR PKD domains 1 and 2Protein Data Bank, 6NZ0.
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Cryo-EM structure of AAV-2 in complex with AAVR PKD domains 1 and 2Unified Data Resource for 3DEM, EMD-0553.
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Structure of the AAV2 with its Cell Receptor AAVRUnified Data Resource for 3DEM, EMD-0621.
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Structure of the AAV2 with its Cell Receptor AAVRUnified Data Resource for 3DEM, EMD-0622.
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Structure of the AAV2 with its Cell Receptor AAVRUnified Data Resource for 3DEM, EMD-0623.
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Structure of the AAV2 with its Cell Receptor AAVRUnified Data Resource for 3DEM, EMD-0624.
Article and author information
Author details
Michael Stewart Chapman
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.
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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