MUTATIONS WHICH INTRODUCE FREE CYSTEINE RESIDUES IN THE GLA-DOMAIN OFVITAMIN-K-DEPENDENT PROTEINS RESULT IN THE FORMATION OF COMPLEXES WITH ALPHA(1)-MICROGLOBULIN
Egc. Wojcik et al., MUTATIONS WHICH INTRODUCE FREE CYSTEINE RESIDUES IN THE GLA-DOMAIN OFVITAMIN-K-DEPENDENT PROTEINS RESULT IN THE FORMATION OF COMPLEXES WITH ALPHA(1)-MICROGLOBULIN, Thrombosis and haemostasis, 75(1), 1996, pp. 70-75
We have previously described a genetic factor IX variant (Cys(18)-->Ar
g) for which we demonstrated that it had formed a heterodimer with alp
ha(1)-microglobulin through formation of a disulphide bond with the re
maining free cysteine residue of the disrupted disulphide bond in the
cia-domain of factor IX. Recently, we observed a similar high molecula
r weight complex for a genetic protein C variant (Arg(-1)-->Cys). Both
the factor IX and the protein C variants have a defect in the calcium
induced conformation. In this study we show that the aminoterminus of
this protein C variant is prolonged with one amino acid, cysteine. Th
is protein C variant, as well as protein C variants with Arg(9)-->Cys
and Ser(12)-->Cys mutations which also carry a free cysteine residue,
are shown to be present in plasma as a complex with alpha(1)-microglob
ulin. A prothrombin variant with a Tyr(44)-->Cys mutation, had not for
med such a complex. Furthermore, complexes between normal vitamin K-de
pendent clotting factors and alpha(1)-microglobulin were shown to be p
resent in plasma at low concentrations. The data suggest that the pres
ence of an unpaired cysteine residue in the propeptide or the N-termin
al half of the Gla-domain has strongly promoted the formation of a com
plex with alpha(1)-microglobulin in the variants.