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Activated protein C cofactor function of protein S: a novel role for a γ-carboxyglutamic acid residue
- Source :
- Blood. 117:6685-6693
- Publication Year :
- 2011
- Publisher :
- American Society of Hematology, 2011.
-
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 ω-loop that mediates Ca2+-dependent phospholipid binding. Using mass spectrometry, it was nevertheless confirmed that Glu36 is γ-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.
- Subjects :
- Models, Molecular
Immunology
Biochemistry
Cofactor
Protein S
Structure-Activity Relationship
chemistry.chemical_compound
Protein structure
Catalytic Domain
Matrix gla protein
medicine
Humans
Protein Interaction Domains and Motifs
Amino Acid Sequence
Cells, Cultured
Factor VIIIa
Gla domain
Binding Sites
biology
Chemistry
Cell Biology
Hematology
Protein Structure, Tertiary
Amino Acid Substitution
Factor Va
biology.protein
Phospholipid Binding
Carboxyglutamic acid
Mutant Proteins
1-Carboxyglutamic Acid
Protein C
Protein Binding
medicine.drug
Subjects
Details
- ISSN :
- 15280020 and 00064971
- Volume :
- 117
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi.dedup.....651a53c49cdc0ee73c3f65bc9c7d9b21