Abstract
High-affinity binding of the trimeric fibre protein to a cell surface primary receptor is a common feature shared by all adenovirus serotypes. Recently, a long elusive species B adenovirus receptor has been identified. Desmoglein 2 (DSG2) a component of desmosomal junction, has been reported to interact at high affinity with Human adenoviruses HAd3, HAd7, HAd11 and HAd14. Little is known with respect to the molecular interactions of adenovirus fibre with the DSG2 ectodomain. By using different DSG2 ectodomain constructs and biochemical and biophysical experiments, we report that the third extracellular cadherin domain (EC3) of DSG2 is critical for HAd3 fibre binding. Unexpectedly, stoichiometry studies using multi-angle laser light scattering (MALLS) and analytical ultra-centrifugation (AUC) revealed a non-classical 1:1 interaction (one DSG2 per trimeric fibre), thus differentiating ‘DSG2-interacting’ adenoviruses from other protein receptor interacting adenoviruses in their infection strategy.
Highlights
Human adenovirus serotypes (HAds) have been classified into seven species (A to G)
To ensure that Desmoglein 2 (DSG2) ectodomain can be produced as a functional protein, we first expressed the whole ectodomain carrying the four cadherin domains (EC1-4) with a C-terminal His-Tag (Fig. 1A)
Since we have previously shown that HAd3 recombinant penton-dodecahedron (Pt-Dd), a dodecahedric particle with twelve fibres, interacts with a commercial DSG2 by surface plasmon resonance (SPR) experiments[6], the functionality of recombinant DSG2
Summary
Human adenovirus serotypes (HAds) have been classified into seven species (A to G). The fibre of multiple serotypes from species A, C, D, E and F (e.g. serotypes 2, 4, 5, 9, 12, 15, 19, 31, 41) has been described to use the coxsackie and adenovirus receptor (CAR) as a primary attachment receptor[2,3]. It has been described that the simultaneous interaction of several knob domains with DSG2, a situation found in the whole virus or in Pt-Dd, which presents 12 fibres per particle, triggers intracellular signalling, and in turn cell membrane remodelling[9,21,22]. This property has been exploited to develop “junction openers” (JOs) which enhance the efficacy of. Based on the stoichiometry of the measured interactions, a non-classical mechanism of HAd3 fibre binding to DSG2 is reported This interaction is a novel binding strategy not observed in other adenovirus/protein receptor complexes such as Ad/CAR and Ad/CD46
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