The Assembly-Activating Protein Promotes Stability and Interactions between AAV’s Viral Proteins to Nucleate Capsid Assembly

Summary: The adeno-associated virus (AAV) vector is a preferred delivery platform for in vivo gene therapy. Natural and engineered variations of the AAV capsid affect a plurality of phenotypes relevant to gene therapy, including vector production and host tropism. Fundamental to these aspects is the...

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Main Authors: Anna C. Maurer, Simon Pacouret, Ana Karla Cepeda Diaz, Jessica Blake, Eva Andres-Mateos, Luk H. Vandenberghe
Format: Article
Language:English
Published: Elsevier 2018-05-01
Series:Cell Reports
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124718305552
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spelling doaj-d96a300cf0694e8cad6fb2c4ad63a8142020-11-24T21:12:02ZengElsevierCell Reports2211-12472018-05-0123618171830The Assembly-Activating Protein Promotes Stability and Interactions between AAV’s Viral Proteins to Nucleate Capsid AssemblyAnna C. Maurer0Simon Pacouret1Ana Karla Cepeda Diaz2Jessica Blake3Eva Andres-Mateos4Luk H. Vandenberghe5Grousbeck Gene Therapy Center, Schepens Eye Research Institute, Massachusetts Eye and Ear, Boston, MA 02114, USA; Ocular Genomics Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USAGrousbeck Gene Therapy Center, Schepens Eye Research Institute, Massachusetts Eye and Ear, Boston, MA 02114, USA; Ocular Genomics Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA; INSERM UMR 1089, University of Nantes, Nantes University Hospital, 22 Boulevard Benoni Goullin, 44200 Nantes, FranceGrousbeck Gene Therapy Center, Schepens Eye Research Institute, Massachusetts Eye and Ear, Boston, MA 02114, USA; Ocular Genomics Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USAGrousbeck Gene Therapy Center, Schepens Eye Research Institute, Massachusetts Eye and Ear, Boston, MA 02114, USA; Ocular Genomics Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USAGrousbeck Gene Therapy Center, Schepens Eye Research Institute, Massachusetts Eye and Ear, Boston, MA 02114, USA; Ocular Genomics Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USAGrousbeck Gene Therapy Center, Schepens Eye Research Institute, Massachusetts Eye and Ear, Boston, MA 02114, USA; Ocular Genomics Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Corresponding authorSummary: The adeno-associated virus (AAV) vector is a preferred delivery platform for in vivo gene therapy. Natural and engineered variations of the AAV capsid affect a plurality of phenotypes relevant to gene therapy, including vector production and host tropism. Fundamental to these aspects is the mechanism of AAV capsid assembly. Here, the role of the viral co-factor assembly-activating protein (AAP) was evaluated in 12 naturally occurring AAVs and 9 putative ancestral capsid intermediates. The results demonstrate increased capsid protein stability and VP-VP interactions in the presence of AAP. The capsid’s dependence on AAP can be partly overcome by strengthening interactions between monomers within the assembly, as illustrated by the transfer of a minimal motif defined by a phenotype-to-phylogeny mapping method. These findings suggest that the emergence of AAP within the Dependovirus genus relaxes structural constraints on AAV assembly in favor of increasing the degrees of freedom for the capsid to evolve. : Maurer et al. describe a phenotype-to-phylogeny mapping strategy correlating phenotypic variation in AAVs to a reconstructed phylogeny, revealing capsid structure-function relationships relevant to that phenotype. Dependence on the viral co-factor AAP for capsid assembly is examined, and capsid functional motifs, in addition to mechanistic roles of AAP, are elucidated. Keywords: AAV, AAP, adeno-associated virus, capsid assembly, manufacturing, capsid, vector engineering, structure-function, gene therapyhttp://www.sciencedirect.com/science/article/pii/S2211124718305552
collection DOAJ
language English
format Article
sources DOAJ
author Anna C. Maurer
Simon Pacouret
Ana Karla Cepeda Diaz
Jessica Blake
Eva Andres-Mateos
Luk H. Vandenberghe
spellingShingle Anna C. Maurer
Simon Pacouret
Ana Karla Cepeda Diaz
Jessica Blake
Eva Andres-Mateos
Luk H. Vandenberghe
The Assembly-Activating Protein Promotes Stability and Interactions between AAV’s Viral Proteins to Nucleate Capsid Assembly
Cell Reports
author_facet Anna C. Maurer
Simon Pacouret
Ana Karla Cepeda Diaz
Jessica Blake
Eva Andres-Mateos
Luk H. Vandenberghe
author_sort Anna C. Maurer
title The Assembly-Activating Protein Promotes Stability and Interactions between AAV’s Viral Proteins to Nucleate Capsid Assembly
title_short The Assembly-Activating Protein Promotes Stability and Interactions between AAV’s Viral Proteins to Nucleate Capsid Assembly
title_full The Assembly-Activating Protein Promotes Stability and Interactions between AAV’s Viral Proteins to Nucleate Capsid Assembly
title_fullStr The Assembly-Activating Protein Promotes Stability and Interactions between AAV’s Viral Proteins to Nucleate Capsid Assembly
title_full_unstemmed The Assembly-Activating Protein Promotes Stability and Interactions between AAV’s Viral Proteins to Nucleate Capsid Assembly
title_sort assembly-activating protein promotes stability and interactions between aav’s viral proteins to nucleate capsid assembly
publisher Elsevier
series Cell Reports
issn 2211-1247
publishDate 2018-05-01
description Summary: The adeno-associated virus (AAV) vector is a preferred delivery platform for in vivo gene therapy. Natural and engineered variations of the AAV capsid affect a plurality of phenotypes relevant to gene therapy, including vector production and host tropism. Fundamental to these aspects is the mechanism of AAV capsid assembly. Here, the role of the viral co-factor assembly-activating protein (AAP) was evaluated in 12 naturally occurring AAVs and 9 putative ancestral capsid intermediates. The results demonstrate increased capsid protein stability and VP-VP interactions in the presence of AAP. The capsid’s dependence on AAP can be partly overcome by strengthening interactions between monomers within the assembly, as illustrated by the transfer of a minimal motif defined by a phenotype-to-phylogeny mapping method. These findings suggest that the emergence of AAP within the Dependovirus genus relaxes structural constraints on AAV assembly in favor of increasing the degrees of freedom for the capsid to evolve. : Maurer et al. describe a phenotype-to-phylogeny mapping strategy correlating phenotypic variation in AAVs to a reconstructed phylogeny, revealing capsid structure-function relationships relevant to that phenotype. Dependence on the viral co-factor AAP for capsid assembly is examined, and capsid functional motifs, in addition to mechanistic roles of AAP, are elucidated. Keywords: AAV, AAP, adeno-associated virus, capsid assembly, manufacturing, capsid, vector engineering, structure-function, gene therapy
url http://www.sciencedirect.com/science/article/pii/S2211124718305552
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