Elucidation of the cause for reduced activity of abnormal human plasmin containing an Ala55‐Thr mutation: importance of highly conserved Ala55 in serine proteases

Abstract

In serine proteases, Ala⁵⁵ 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 Ala⁵⁵ in catalysis. In the present study, the 3‐D model of A55T human plasmin shows that an unusual hydrogen bond between Thr⁵⁵ Oγ1 and His⁵⁷ Nϵ2 alters His⁵⁷ into an inactive conformation in which His⁵⁷ cannot accept a proton from Ser¹⁹⁵ as a catalytic base. Our results demonstrate that Ala⁵⁵ contributes heavily to the active conformation of His⁵⁷ and ensures the proton transfer from Ser¹⁹⁵ to His⁵⁷.