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Published on: October 26, 2018
Conservation of fiber structure and CD46 usage by subgroup B2 adenoviruses
Lars Pache1, Sangita Venkataraman, Glen R Nemerow
1Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Abstract:
Most subgroup B2 adenoviruses use CD46 as their primary receptor. Recent structural and mutagenesis studies suggested that Ad11 and Ad35 likely engage this receptor in a very similar fashion. However, no comparative studies assessing the cell-associated CD46 binding efficiencies of different Ad fibers have been performed. We solved the crystal structure of Ad35 fiber knob and constructed a model of the fiber knob complexed with CD46. Comparison of our model with that of Ad11-CD46 showed that despite a larger CD46-interacting region in the IJ loop of Ad11, the buried surface area was very similar, suggesting that both fiber knobs might exhibit similar binding. In support of this, cell based competition studies demonstrated almost identical binding efficiencies of Ad11 and Ad35 fibers to cell surface CD46. These findings shed further light on CD46 association by Ad and could impact the selection of novel Ad types for gene transfer.
Insights
Subgroup B2 adenoviruses, like Ad11 and Ad35, bind to CD46. Comparative studies show Ad11 and Ad35 fibers have similar binding efficiencies to cell-associated CD46, impacting gene transfer vector selection.
Area of Science:
- Virology
- Structural Biology
- Molecular Interactions
Background:
- Subgroup B2 adenoviruses (Ads) primarily utilize CD46 as their cellular receptor.
- Previous research indicated similar binding mechanisms for Ad11 and Ad35 to CD46.
- No direct comparative studies quantified the binding efficiencies of different Ad fibers to cell-associated CD46.
Purpose of the Study:
- To structurally analyze the Ad35 fiber knob-CD46 interaction.
- To compare the CD46 binding efficiencies of Ad11 and Ad35 fibers.
- To elucidate the molecular basis of CD46-adenovirus interactions.
Main Methods:
- X-ray crystallography to determine the Ad35 fiber knob structure.
- Computational modeling to create an Ad35 fiber knob-CD46 complex model.
- Cell-based competition assays to assess binding affinities.
Main Results:
- The crystal structure of the Ad35 fiber knob was solved.
- A comparative model of Ad11-CD46 interaction revealed similar buried surface areas despite differences in the interacting regions.
- Cell-based assays demonstrated nearly identical binding efficiencies for Ad11 and Ad35 fibers to cell surface CD46.
Conclusions:
- Ad11 and Ad35 fibers exhibit comparable binding affinities for cell-associated CD46.
- Structural similarities and functional data suggest a conserved binding mode for these adenoviruses to CD46.
- These findings have implications for selecting adenovirus serotypes for gene therapy applications.
