Molecular mechanism of α2β1 integrin interaction with human echovirus 1

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Abstract
Conformational activation increases the affinity of integrins to their ligands. On ligand binding, further changes in integrin conformation elicit cellular signalling. Unlike any of the natural ligands of alpha 2 beta 1 integrin, human echovirus 1 (EV1) seemed to bind more avidly a 'closed' than an activated 'open' form of the alpha 2I domain. Furthermore, a mutation E336A in the alpha 2 subunit, which inactivated alpha 2 beta 1 as a collagen receptor, enhanced alpha 2 beta 1 binding to EV1. Thus, EV1 seems to recognize an inactive integrin, and not even the virus binding could trigger the conformational activation of alpha 2 beta 1. This was supported by the fact that the integrin clustering by EV1 did not activate the p38 MAP kinase pathway, a signalling pathway that was shown to be dependent on E336-related conformational changes in alpha 2 beta 1. Furthermore, the mutation E336A did neither prevent EV1 induced and alpha 2 beta 1 mediated protein kinase C activation nor EV1 internalization. Thus, in its entry strategy EV1 seems to rely on the activation of signalling pathways that are dependent on alpha 2 beta 1 clustering, but do not require the conformational regulation of the receptor. The EMBO Journal (2010) 29, 196-208. doi: 10.1038/emboj.2009.326; Published online 19 November 2009