Molecular features of the integrin receptor and its interaction with the FMDV, an in silico study

MARRERO DIAZ DE VILLEGAS, RUBEN; GISMONDI, MARÍA INÉS; KÖNIG, GUIDO A.

Bangkok

Congreso; Global Foot-and-Mouth Disease Research Alliance 2019 Scientific Meeting; 2019

Global Foot-and-Mouth Disease Research Alliance

Foot and Mouth Disease is an agro-economic relevant threat caused by a picornavirus (FMDV) which affects wild and domestic cloven-hoofed animals. At a molecular level, the viral entrance takes place due to host-pathogen interactions, mainly between a FMDV capsid motif (aminoacidic triplet RGD) and cell adhesion molecules, integrins (IT). This landscape is further complex indeed; FMDV not only displays a mere integrin recognition motif at their capsid surface, but evolved its RGD aminoacidic surroundings for a high affinity to a specific αVβ6 IT receptor, highly expressed in nasopharynx tissues which are the primary infection site. Our aim has been to study the amino acid usage at the αVβ6 IT that determines physicochemical features of great affinity for the FMDV surface at the RGD motif and its context.The recent resolution of the quasi-atomic structure of the human αVβ6 integrin, in complex with an RGD peptide, has paved an avenue for diverse structural studies. Herein, we take advantage of this work of reference and computationally explored the full αVβ6 amino acidic sequence space at the interaction interface with RGD peptide. Our results were of great concordance with previous experimental reports and further points out some novel features of potential relevance for such interaction phenomenon. Next, we move up to the bovine host and in silico modeled several bovine αVβx ITs in complex with an RGD FMDV peptide, and fully studied (by single mutants) the preferred aminoacidic substitutions at the interaction interface. The emergent data shows, in a homologous mode with the human model, that the bovine integrins αVβ6 preferentially presents a unique hydrophobic interface (amino acids usage) which supports their specificity for the alfa helix presented at the end of the RGD peptide. Other IT subunits (β3 and β5) at the same interaction interface residues, present more polar or bulky amino acids which result in a less compatible interaction.In summary, our work builds on previous structures to recapitulate the bovine model and bring information concerning the specificity determinants of the recognition between FMDV and bovine integrins. We have also described the preferred sequence space of the bovine integrins for any peptide.