Cargando…
Structure of the gene therapy vector, adeno-associated virus with its cell receptor, AAVR
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-...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561701/ https://www.ncbi.nlm.nih.gov/pubmed/31115336 http://dx.doi.org/10.7554/eLife.44707 |
_version_ | 1783426175164481536 |
---|---|
author | Meyer, Nancy L Hu, Guiqing Davulcu, Omar Xie, Qing Noble, Alex J Yoshioka, Craig Gingerich, Drew S Trzynka, Andrew David, Larry Stagg, Scott M Chapman, Michael Stewart |
author_facet | Meyer, Nancy L Hu, Guiqing Davulcu, Omar Xie, Qing Noble, Alex J Yoshioka, Craig Gingerich, Drew S Trzynka, Andrew David, Larry Stagg, Scott M Chapman, Michael Stewart |
author_sort | Meyer, Nancy L |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6561701 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-65617012019-06-13 Structure of the gene therapy vector, adeno-associated virus with its cell receptor, AAVR Meyer, Nancy L Hu, Guiqing Davulcu, Omar Xie, Qing Noble, Alex J Yoshioka, Craig Gingerich, Drew S Trzynka, Andrew David, Larry Stagg, Scott M Chapman, Michael Stewart eLife Microbiology and Infectious Disease 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. eLife Sciences Publications, Ltd 2019-05-22 /pmc/articles/PMC6561701/ /pubmed/31115336 http://dx.doi.org/10.7554/eLife.44707 Text en © 2019, Meyer et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Microbiology and Infectious Disease Meyer, Nancy L Hu, Guiqing Davulcu, Omar Xie, Qing Noble, Alex J Yoshioka, Craig Gingerich, Drew S Trzynka, Andrew David, Larry Stagg, Scott M Chapman, Michael Stewart Structure of the gene therapy vector, adeno-associated virus with its cell receptor, AAVR |
title | Structure of the gene therapy vector, adeno-associated virus with its cell receptor, AAVR |
title_full | Structure of the gene therapy vector, adeno-associated virus with its cell receptor, AAVR |
title_fullStr | Structure of the gene therapy vector, adeno-associated virus with its cell receptor, AAVR |
title_full_unstemmed | Structure of the gene therapy vector, adeno-associated virus with its cell receptor, AAVR |
title_short | Structure of the gene therapy vector, adeno-associated virus with its cell receptor, AAVR |
title_sort | structure of the gene therapy vector, adeno-associated virus with its cell receptor, aavr |
topic | Microbiology and Infectious Disease |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561701/ https://www.ncbi.nlm.nih.gov/pubmed/31115336 http://dx.doi.org/10.7554/eLife.44707 |
work_keys_str_mv | AT meyernancyl structureofthegenetherapyvectoradenoassociatedviruswithitscellreceptoraavr AT huguiqing structureofthegenetherapyvectoradenoassociatedviruswithitscellreceptoraavr AT davulcuomar structureofthegenetherapyvectoradenoassociatedviruswithitscellreceptoraavr AT xieqing structureofthegenetherapyvectoradenoassociatedviruswithitscellreceptoraavr AT noblealexj structureofthegenetherapyvectoradenoassociatedviruswithitscellreceptoraavr AT yoshiokacraig structureofthegenetherapyvectoradenoassociatedviruswithitscellreceptoraavr AT gingerichdrews structureofthegenetherapyvectoradenoassociatedviruswithitscellreceptoraavr AT trzynkaandrew structureofthegenetherapyvectoradenoassociatedviruswithitscellreceptoraavr AT davidlarry structureofthegenetherapyvectoradenoassociatedviruswithitscellreceptoraavr AT staggscottm structureofthegenetherapyvectoradenoassociatedviruswithitscellreceptoraavr AT chapmanmichaelstewart structureofthegenetherapyvectoradenoassociatedviruswithitscellreceptoraavr |