Elucidation of the cause for reduced activity of abnormal human plasmin containing an Ala 55-Thr mutation: importance of highly conserved Ala 55 in serine proteases

Abstract

In serine proteases, Ala 55 is highly conserved and located just behind the catalytic triad. That the activity of human plasmin is reduced by the A55T substitution indicates the importance of Ala 55 in catalysis. In the present study, the 3-D model of A55T human plasmin shows that an unusual hydrogen bond between Thr 55 Oγ1 and His 57 Nϵ2 alters His 57 into an inactive conformation in which His 57 cannot accept a proton from Ser 195 as a catalytic base. Our results demonstrate that Ala 55 contributes heavily to the active conformation of His 57 and ensures the proton transfer from Ser 195 to His 57.