Deletion or replacement of the second EGF-like domain of protein S results in loss of APC cofactor activity
Human protein S (PS), a cofactor of anticoagulant-activated protein C (APC), is a modular protein containing 4 epidermal growth factor (EGF)–like domains. EGF1 appears to mediate PS interaction with APC, but the roles of EGFs 2, 3, and 4 are less clear. We synthesized PS variants lacking single EGF...
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Veröffentlicht in: | Blood 2003-02, Vol.101 (4), p.1416-1418 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | Human protein S (PS), a cofactor of anticoagulant-activated protein C (APC), is a modular protein containing 4 epidermal growth factor (EGF)–like domains. EGF1 appears to mediate PS interaction with APC, but the roles of EGFs 2, 3, and 4 are less clear. We synthesized PS variants lacking single EGF domains (EGF2, 3, or 4) and assessed their APC cofactor activity in a factor Va inactivation assay. The variant lacking EGF2 (variant 134) showed the most dramatic loss of activity (∼10% of recombinant wild-type PS activity). Replacement of EGF2 by an additional EGF3 (variant 1334) resulted in a comparable loss of activity, suggesting that the loss of a specific rather than “spacer” function of EGF2 was responsible. We confirmed that the variant 134 had a functional γ-carboxyglutamic acid (Gla) domain and that EGF1 was correctly folded. This is the first clear evidence that EGF2 is required for the expression of PS activity. |
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ISSN: | 0006-4971 1528-0020 |
DOI: | 10.1182/blood-2002-08-2353 |