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Blood, 1 January 2005, Vol. 105, No. 1, pp. 1-2.
Gla glances at proteinsCARDIOVASCULAR RESEARCH INSTITUTE MAASTRICHT
Our view on Gla domains can no longer be limited to their phospholipid-binding properties because they cointeract directly with proteins, and as is shown for protein S in this issue, these interactions are mediated by distinct faces on the Gla domain.
In the late 1970s, 2 models of Gla-binding to phospholipids were proposed: the ionic interaction model assumed that Gla-bound Ca2+ ions were involved in negatively charged membrane binding through electrostatic interactions, and the chelation model proposed coordination of Ca2+ between one Gla residue and 2 negatively charged phosphatidylserine head groups. In 1995, Sunnerhagen et al1 described Ca2+-induced exposure of hydrophobic residues in the
In the past decade, however, increasing evidence emerged for interactions of Gla domains with ligands other than phospholipids. Examples include binding of the Gla domains of activated protein C (APC) to the endothelial cell protein C receptor (EPCR),3 of activated factor IX (FIXa) to activated factor VIII (FVIIIa),4 and of factor X to tissue factor-factor VIIa.5
In this issue, Saller and colleagues identified 2 faces on the Gla domain of protein S that mediate interactions with phospholipids and APC, respectively. The clue for unraveling these faces followed from the application of a protein S molecule, in which the Gla domain was exchanged for the Gla domain of prothrombin. This prothrombin–protein S chimera retained phospholipid binding capacity but did not act as a cofactor for APC, explained by a loss of interaction with APC. Using homology modeling and differences in sequence between the Gla domains of prothrombin and protein S, 2 opposite faces were postulated; the solvent-exposed residues were either involved in the interaction with phospholipids (face 1) or APC (face 2). In a solvent-accessible surface model it is clearly shown that the important residues of the faces are exposed on opposite sides of the Gla domain of protein S (figure). Replacing face 2 in protein S with the amino acids from prothrombin resulted in loss of APC-cofactor activity, and reintroducing the faces from protein S in the prothrombin–protein S chimera regained previously lost APC-cofactor activity, and therefore likely the interaction with APC. Protein S is a multimodular protein that is special among the vitamin K–dependent coagulation protein family as it is not a precursor to an enzyme. It is a multifunctional protein and is most well known for its cofactor activity to APC. In addition, protein S regulates thrombin formation in the absence of APC, is involved in inflammatory mediation and apoptosis pathways, and exhibits neuroprotective effects.6 In aid of structure-function analysis of these different activities of protein S, it is important to locate regions or residues within protein S that govern specific activities. For the first time in protein S, such residues are identified, which may serve as a stepping stone for unraveling mechanistic bases that differentiate between multiple functions of this essential protein. References
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| Copyright © 2005 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
-carboxyglutamic acid (Gla)–rich modules were considered solely to be membrane anchors that enabled vitamin K–dependent clotting factors to interact with (negatively charged) phospholipid surfaces. On these surfaces, the enzyme-cofactor complexes can effectively exert their pro- and anticoagulant activities. 
-loop to be essential for membrane binding.
