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Background  Factor  XI  ( FXI ) is a zymogen in the coagulation pathway that, once activated, promotes haemostasis by activating factor  IX  ( FIX ). Substitution studies using apple domains of the homologous protein prekallikrein have identified that  FIX  binds to the apple 3 domain of  FXI . However, the molecular changes upon activation of  FXI  or binding of  FIX  to  FXI a have remained largely unresolved.    Objectives  This study aimed to gain more insight in the  FXI  activation mechanism by identifying the molecular differences between  FXI  and  FXI a, and in the conformational changes in  FXI a induced by binding of  FIX .    Methods  Hydrogen‐deuterium exchange mass spectrometry was performed on  FXI ,  FXI a, and  FXI a in complex with  FIX .    Results  Both activation and binding to  FIX  induced conformational changes at the interface between the catalytic domain and the apple domains of  FXI (a)—more specifically at the loops connecting the apple domains. Moreover, introduction of  FIX  uniquely induced a reduction of deuterium uptake in the beginning of the apple 3 domain.    Conclusions  We propose that the conformational changes of the catalytic domain upon activation increase the accessibility to the apple 3 domain to enable  FIX  binding. Moreover, our  HDX MS  results support the location of the proposed  FIX  binding site at the beginning of the apple 3 domain and suggest a mediating role in  FIX  binding for both loops adjacent to the apple 3 domain.

journal of thrombosis and haemostasis

Hydrogen‐deuterium exchange mass spectrometry highlights conformational changes induced by factor  XI  activation and binding of factor  IX  to factor  XI a