Common coding variant in SERPINA1 increases the risk for large artery stroke
Malik R., Dau T., Gonik M., Sivakumar A., Deredge DJ., Edeleva EV., Götzfried J., van der Laan SW., Pasterkamp G., Beaufort N., Seixas S., Bevan S., Lincz LF., Holliday EG., Burgess AI., Rannikmäe K., Minnerup J., Kriebel J., Waldenberger M., Müller-Nurasyid M., Lichtner P., Saleheen D., Rothwell PM., Levi C., Attia J., Sudlow CLM., Braun D., Markus HS., Wintrode PL., Berger K., Jenne DE., Dichgans M., Woo D., Debette S., Maguire J., Cole JW., Majersik J., Bevan S., Jimenez-Conde J., Lee J-M., Rost N., Pare G., Jern C., Lindgren AG., Cardenas IF.
Significance Common single-amino acid variations of proteins are traditionally regarded as functionally neutral polymorphisms because these substitutions are mostly located outside functionally relevant surfaces. In this study, we present an example of a functionally relevant coding sequence variation, which, as we show here, confers risk for large artery atherosclerotic stroke. The single-residue variation M1(A213V) in serpin family A member 1 ( SERPINA1 ) [encoding alpha-1 antitrypsin (AAT)] is situated outside the protease-reactive inhibitory loop and is found in a β-turn on the protein surface. We show that the Ala-to-Val exchange in the gate region of AAT alters its functional dynamics toward neutrophil elastase in the presence of complex lipid-containing plasma and also affects the overall structural flexibility of the protein.