The propeptides of the vitamin K-dependent proteins possess different affinities for the vitamin K-dependent carboxylase

被引:74
作者
Stanley, TB [1 ]
Jin, DY [1 ]
Lin, PJ [1 ]
Stafford, DW [1 ]
机构
[1] Univ N Carolina, Dept Biol, Ctr Thrombosis & Hemostasis, Chapel Hill, NC 27599 USA
关键词
D O I
10.1074/jbc.274.24.16940
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The vitamin K-dependent gamma-glutamyl carboxylase catalyzes the modification of specific glutamates in a number of proteins required for blood coagulation and associated with bone and calcium homeostasis. All known vitamin K-dependent proteins possess a conserved eighteen-amino acid propeptide sequence that is the primary binding site for the carboxylase, We compared the relative affinities of synthetic propeptides of nine human vitamin R-dependent proteins by determining the inhibition constants (K-i) toward a factor IX propeptide/gamma-carboxyglutamic acid domain substrate. The Ki values for six of the propeptides (factor X, matrix Gla protein, factor VII, factor IX, PRGP1, and protein S) were between 2-35 nM, with the factor X propeptide having the tightest affinity. In contrast, the inhibition constants for the propeptides of prothrombin and protein C are similar to 100-fold weaker than the factor X propeptide, The propeptide of bone Gla protein demonstrates severely impaired carboxylase binding with an inhibition constant of at least 200,000-fold weaker than the factor X propeptide, This study demonstrates that the affinities of the propeptides of the vitamin K-dependent proteins vary over a considerable range; this may have important physiological consequences in the levels of vitamin K-dependent proteins and the biochemical mechanism by which these substrates are modified by the carboxylase.
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页码:16940 / 16944
页数:5
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