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

eLife

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[1] Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, United States;Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, United States;Department of Biochemistry, University of Missouri, Columbia, United States;Institute Molecular Biophysics, Florida State University, Tallahassee, United States;Institute Molecular Biophysics, Florida State University, Tallahassee, United States;Department of Chemistry and Biochemistry, Florida State University, Tallahassee, United States;OHSU Center for Spatial Systems Biomedicine, Portland, United States;

关键词: electron microscopy;    viral vector;    human;    atomic;    entry;    trafficking;    Virus;   

DOI  :  10.7554/eLife.44707

来源: publisher

【 摘 要 】

10.7554/eLife.44707.001Adeno-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.

【 授权许可】

CC BY