NDLI: Activated protein C cofactor function of protein S: a critical role for Asp95 in the EGF1-like domain

Content Provider	PubMed Central
Author	Andersson, Helena M. Arantes, Márcia J. Crawley, James T. B. Luken, Brenda M. Tran, Sinh Dahlbäck, Björn Lane, David A. Rezende, Suely M.
Copyright Year	2010
Abstract	Protein S has an established role in the protein C anticoagulant pathway, where it enhances the factor Va (FVa) and factor VIIIa (FVIIIa) inactivating property of activated protein C (APC). Despite its physiological role and clinical importance, the molecular basis of its action is not fully understood. To clarify the mechanism of the protein S interaction with APC, we have constructed and expressed a library of composite or point variants of human protein S, with residue substitutions introduced into the Gla, thrombin-sensitive region (TSR), epidermal growth factor 1 (EGF1), and EGF2 domains. Cofactor activity for APC was evaluated by calibrated automated thrombography (CAT) using protein S–deficient plasma. Of 27 variants tested initially, only one, protein S D95A (within the EGF1 domain), was largely devoid of functional APC cofactor activity. Protein S D95A was, however, γ-carboxylated and bound phospholipids with an apparent dissociation constant (Kdapp) similar to that of wild-type (WT) protein S. In a purified assay using FVa R506Q/R679Q, purified protein S D95A was shown to have greatly reduced ability to enhance APC-induced cleavage of FVa Arg306. It is concluded that residue Asp95 within EGF1 is critical for APC cofactor function of protein S and could define a principal functional interaction site for APC.
Related Links	http://dx.doi.org/10.1182/blood-2009-11-256610
Ending Page	4885
Page Count	8
Starting Page	4878
File Format	PDF
ISSN	00064971
e-ISSN	15280020
Journal	Blood
Issue Number	23
Volume Number	115
Language	English
Publisher	American Society of Hematology
Publisher Date	2010-06-10
Access Restriction	Open
Rights Holder	American Society of Hematology
Subject Keyword	Immunology Cell Biology Biochemistry Hematology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Hematology Biochemistry Immunology

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