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Activated protein C cofactor function of protein S: a novel role for a gamma-carboxyglutamic acid residue

Ahnström, Josefin LU ; Andersson, Helena ; Canis, Kevin ; Norström, Eva LU ; Yu, Yao ; Dahlbäck, Björn LU ; Panico, Maria ; Morris, Howard R. ; Crawley, James T. B. and Lane, David A. (2011) In Blood 117(24). p.6685-6693
Abstract
Protein S has an important anticoagulant function by acting as a cofactor for activated protein C (APC). We recently reported that the EGF1 domain residue Asp95 is critical for APC cofactor function. In the present study, we examined whether additional interaction sites within the Gla domain of protein S might contribute to its APC cofactor function. We examined 4 residues, composing the previously reported "Face1" (N33S/P35T/E36A/Y39V) variant, as single point substitutions. Of these protein S variants, protein S E36A was found to be almost completely inactive using calibrated automated thrombography. In factor Va inactivation assays, protein S E36A had 89% reduced cofactor activity compared with wild-type protein S and was almost... (More)
Protein S has an important anticoagulant function by acting as a cofactor for activated protein C (APC). We recently reported that the EGF1 domain residue Asp95 is critical for APC cofactor function. In the present study, we examined whether additional interaction sites within the Gla domain of protein S might contribute to its APC cofactor function. We examined 4 residues, composing the previously reported "Face1" (N33S/P35T/E36A/Y39V) variant, as single point substitutions. Of these protein S variants, protein S E36A was found to be almost completely inactive using calibrated automated thrombography. In factor Va inactivation assays, protein S E36A had 89% reduced cofactor activity compared with wild-type protein S and was almost completely inactive in factor VIIIa inactivation; phospholipid binding was, however, normal. Glu36 lies outside the omega-loop that mediates Ca2+-dependent phospholipid binding. Using mass spectrometry, it was nevertheless confirmed that Glu36 is gamma-carboxylated. Our finding that Gla36 is important for APC cofactor function, but not for phospholipid binding, defines a novel function (other than Ca2+ coordination/phospholipid binding) for a Gla residue in vitamin K-dependent proteins. It also suggests that residues within the Gla and EGF1 domains of protein S act cooperatively for its APC cofactor function. (Blood. 2011;117(24):6685-6693) (Less)
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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Blood
volume
117
issue
24
pages
6685 - 6693
publisher
American Society of Hematology
external identifiers
  • wos:000291684300036
  • scopus:79959187738
  • pmid:21508412
ISSN
1528-0020
DOI
10.1182/blood-2010-11-317099
language
English
LU publication?
yes
id
f9b75e28-b537-41ed-bbbd-5a3f9623e519 (old id 2056814)
date added to LUP
2016-04-01 09:49:15
date last changed
2025-04-04 14:05:49
@article{f9b75e28-b537-41ed-bbbd-5a3f9623e519,
  abstract     = {{Protein S has an important anticoagulant function by acting as a cofactor for activated protein C (APC). We recently reported that the EGF1 domain residue Asp95 is critical for APC cofactor function. In the present study, we examined whether additional interaction sites within the Gla domain of protein S might contribute to its APC cofactor function. We examined 4 residues, composing the previously reported "Face1" (N33S/P35T/E36A/Y39V) variant, as single point substitutions. Of these protein S variants, protein S E36A was found to be almost completely inactive using calibrated automated thrombography. In factor Va inactivation assays, protein S E36A had 89% reduced cofactor activity compared with wild-type protein S and was almost completely inactive in factor VIIIa inactivation; phospholipid binding was, however, normal. Glu36 lies outside the omega-loop that mediates Ca2+-dependent phospholipid binding. Using mass spectrometry, it was nevertheless confirmed that Glu36 is gamma-carboxylated. Our finding that Gla36 is important for APC cofactor function, but not for phospholipid binding, defines a novel function (other than Ca2+ coordination/phospholipid binding) for a Gla residue in vitamin K-dependent proteins. It also suggests that residues within the Gla and EGF1 domains of protein S act cooperatively for its APC cofactor function. (Blood. 2011;117(24):6685-6693)}},
  author       = {{Ahnström, Josefin and Andersson, Helena and Canis, Kevin and Norström, Eva and Yu, Yao and Dahlbäck, Björn and Panico, Maria and Morris, Howard R. and Crawley, James T. B. and Lane, David A.}},
  issn         = {{1528-0020}},
  language     = {{eng}},
  number       = {{24}},
  pages        = {{6685--6693}},
  publisher    = {{American Society of Hematology}},
  series       = {{Blood}},
  title        = {{Activated protein C cofactor function of protein S: a novel role for a gamma-carboxyglutamic acid residue}},
  url          = {{http://dx.doi.org/10.1182/blood-2010-11-317099}},
  doi          = {{10.1182/blood-2010-11-317099}},
  volume       = {{117}},
  year         = {{2011}},
}