Characterization of a heparin-binding site on the catalytic domain of factor XIa: mechanism of heparin acceleration of factor XIa inhibition by the serpins antithrombin and C1-inhibitor.

ABSTRACT: Heparin accelerates inhibition of factor XIa (fXIa) by the serpins antithrombin (AT) and C1-inhibitor (C1-INH) by more than 2 orders of magnitude. The mechanism of the heparin-mediated acceleration of fXIa inhibition by these serpins is incompletely understood, as heparin appears to interact with both the catalytic and noncatalytic domains of the protease. We replaced the basic residues of the fXIa 170 loop (Lys-170, Arg-171, Arg-173, Lys-175, and Lys-179; chymotrypsin numbering) with Ala, using an expression system that allows separation of the fXIa catalytic domain (CD) from noncatalytic domains. Heparin-mediated inhibition of 170 loop CD variants with AT was impaired 3-10-fold relative to that of the wild-type (CD-WT). In reactions with C1-INH, Arg-171 was the most critical residue cont

SUBMITTER: Yang L 

PROVIDER: S-EPMC2654577 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature