Interactions outside the proteinase-binding loop contribute significantly to the inhibition of activated coagulation factor XII by its canonical inhibitor from cornстатья

Статья опубликована в высокорейтинговом журнале

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[1] Interactions outside the proteinase-binding loop contribute significantly to the inhibition of activated coagulation factor xii by its canonical inhibitor from corn / V. A. Korneeva, M. M. Trubetskov, A. V. Korshunova et al. // Journal of Biological Chemistry. — 2014. — Vol. 289, no. 20. — P. 14109–14120. Activated factor XII (FXIIa) is selectively inhibited by corn Hageman factor inhibitor (CHFI) among other plasma proteases. CHFI is considered a canonical serine protease inhibitor that interacts with FXIIa through its protease-binding loop. Here we examined whether the protease-binding loop alone is sufficient for the selective inhibition of serine proteases or whether other regions of a canonical inhibitor are involved. Six CHFI mutants lacking different N- and C-terminal portions were generated. CHFI-234, which lacks the first and fifth disulfide bonds and 11 and 19 amino acid residues at the N and C termini, respectively, exhibited no significant changes in FXIIa inhibition (Ki = 3.2 +/- 0.4 nm). CHFI-123, which lacks 34 amino acid residues at the C terminus and the fourth and fifth disulfide bridges, inhibited FXIIa with a Ki of 116 +/- 16 nm. To exclude interactions outside the FXIIa active site, a synthetic cyclic peptide was tested. The peptide contained residues 20-45 (Protein Data Bank code 1BEA), and a C29D substitution was included to avoid unwanted disulfide bond formation between unpaired cysteines. Surprisingly, the isolated protease-binding loop failed to inhibit FXIIa but retained partial inhibition of trypsin (Ki = 11.7 +/- 1.2 mum) and activated factor XI (Ki = 94 +/- 11 mum). Full-length CHFI inhibited trypsin with a Ki of 1.3 +/- 0.2 nm and activated factor XI with a Ki of 5.4 +/- 0.2 mum. Our results suggest that the protease-binding loop is not sufficient for the interaction between FXIIa and CHFI; other regions of the inhibitor also contribute to specific inhibition. [ DOI ]

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