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Common coding variant in SERPINA1 increases the risk for large artery stroke

2017; National Academy of Sciences; Volume: 114; Issue: 14 Linguagem: Inglês

10.1073/pnas.1616301114

1091-6490

Rainer Malik, Therese Dau, Maria Gonik, Anirudh Sivakumar, Daniel Deredge, Evgeniia Edeleva, Jessica Götzfried, Sander W. van der Laan, Gerard Pasterkamp, Nathalie Beaufort, Susana Seixas, Steve Bevan, Lisa F. Lincz, Elizabeth Holliday, A I Burgess, Kristiina Rannikmäe, Jens Minnerup, Jennifer Kriebel, Mélanie Waldenberger, Martina Müller‐Nurasyid, Peter Lichtner, Danish Saleheen, Peter M. Rothwell, Christopher Levi, John Attia, Cathie Sudlow, Dieter Braun, Hugh S. Markus, Patrick L. Wintrode, Klaus Berger, Dieter E. Jenne, Martin Dichgans, Daniel Woo, Stéphanie Debette, Jane Maguire, John W. Cole, Jennifer J. Majersik, Steve Bevan, Jordi Jiménez-Conde, Jin‐Moo Lee, Natalia S. Rost, Guillaume Paré, Christina Jern, Arne Lindgren, I. Cardenas,

Calpain Protease Function and Regulation

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.