Completion of the AAV Structural Atlas: Serotype Capsid Structures Reveals Clade-Specific Features.

Mario Mietzsch,Nadia Daneshparvar,Mavis Agbandje-Mckenna,Paul Chipman,Robert Mckenna,Ariana Jose,Nilakshee Bhattacharya

doi:10.3390/v13010101

Mario Mietzsch, Nadia Daneshparvar + Show 5 more

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https://doi.org/10.3390/v13010101

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Journal: Viruses	Publication Date: Jan 13, 2021
Citations: 50	License type: CC BY 4.0

Affiliation: University of Florida, Florida State University

Abstract

The capsid structures of most Adeno-associated virus (AAV) serotypes, already assigned to an antigenic clade, have been previously determined. This study reports the remaining capsid structures of AAV7, AAV11, AAV12, and AAV13 determined by cryo-electron microscopy and three-dimensional image reconstruction to 2.96, 2.86, 2.54, and 2.76 Å resolution, respectively. These structures complete the structural atlas of the AAV serotype capsids. AAV7 represents the first clade D capsid structure; AAV11 and AAV12 are of a currently unassigned clade that would include AAV4; and AAV13 represents the first AAV2-AAV3 hybrid clade C capsid structure. These newly determined capsid structures all exhibit the AAV capsid features including 5-fold channels, 3-fold protrusions, 2-fold depressions, and a nucleotide binding pocket with an ordered nucleotide in genome-containing capsids. However, these structures have viral proteins that display clade-specific loop conformations. This structural characterization completes our three-dimensional library of the current AAV serotypes to provide an atlas of surface loop configurations compatible with capsid assembly and amenable for future vector engineering efforts. Derived vectors could improve gene delivery success with respect to specific tissue targeting, transduction efficiency, antigenicity or receptor retargeting.

Highlights

Adeno-associated viruses (AAV) are single-stranded DNA packaging viruses of the Parvoviridae and belong to the genus Dependoparvovirus [1]
AAV10, a member of clade E [3], possesses just a single amino acid difference (A589T) within VP3 compared to AAVrh.39, EMD-23201/PDB ID 7L6B (AAV12 empty), EMD-23204/PDB ID 7L6H (AAV13 full), EMD-23205/PDB ID 7L6I (AAV13 empty), respectively
This study determined the capsid structures of AAV7, AAV11, AAV12, and AAV13, thereby completing the panel of available structures for all currently defined AAV serotypes

Summary

Introduction

Adeno-associated viruses (AAV) are single-stranded DNA packaging viruses of the Parvoviridae and belong to the genus Dependoparvovirus [1]. The virions of the AAVs are composed of non-enveloped capsids with T = 1 icosahedral symmetry and diameters of ≈260 Å [4]. They are assembled from 60 viral proteins (VPs): VP1 (≈82 kDa), VP2 (≈73 kDa), and VP3 (≈61 kDa) in an approximate 1:1:10 ratio [5]. Compared to VP3, VP1 and VP2 are extended at their N-termini with a shared ≈65 amino acid (aa) region and additional ≈137 aa N-terminal to VP2 in the case of VP1 (VP1u). The VP1 amino acid sequence identity of the AAV serotypes varies between 57 and 99% [8]

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Conclusion