Gla residues and calcium-dependent anchoring of clotting factors
Gla residues are glutamate amino acids given an extra carboxyl group (a COOH chemical group); they bind calcium and anchor vitamin K-dependent clotting factors to platelet phospholipid.
Remember
Calcium is the bridge: Gla residues bind it, and it links vitamin K-dependent clotting factors to phospholipid on activated platelets (platelets switched on by vessel damage), which keeps clotting at the injury.
Memory aid
Gla is the anchor, calcium is the bridge, and the platelet surface is the dock.
Use it to recall the order of the link: the Gla domain, then calcium, then the platelet surface.
Several clotting proteins are made in the liver, including prothrombin (factor II, the inactive precursor of the enzyme thrombin) and factors VII, IX and X. The liver adds an extra carboxyl group to glutamate amino acids in these proteins, in a step that needs vitamin K. This is called post-translational modification, because it happens after the protein is made. The modified amino acids are Gla residues, short for gamma-carboxyglutamate, and a cluster of them forms a Gla domain.
The extra carboxyl groups carry a negative charge, so they bind positively charged calcium ions. Calcium then works as a bridge between the Gla domain and negatively charged phospholipids, such as phosphatidylserine (a fatty membrane molecule), on the surface of activated platelets (platelets switched on by vessel damage). Because those surfaces are exposed mainly at the injury, the clotting factors gather there.
On that surface, factor Xa (the enzyme) and its helper protein, factor Va, form the prothrombinase complex. This converts prothrombin to thrombin much more efficiently than the enzyme does when it is free in solution. Thrombin then cleaves fibrinogen to give fibrin. Only prothrombin next to the damage is activated, so the clot stays localised to the injury.
Warfarin (a drug that blocks vitamin K recycling) means that newly made clotting factors have fewer working Gla residues. They are still made, but they bind calcium badly and assemble poorly on platelets, so thrombin generation falls and bleeding can follow.
Key facts
- Which factors
- prothrombin (factor II) and factors VII, IX and X are the procoagulant (clot-promoting) factors that carry Gla domains.
- Vitamin K step
- the liver adds the extra carboxyl group to glutamate in a step that needs vitamin K.
- Calcium bridge
- calcium links the Gla domain to negatively charged phospholipid on activated platelets.
- Localisation
- the phospholipid surface is exposed where platelets are activated, so factors are gathered next to the damage rather than throughout the blood.
- Enzyme part
- in prothrombin the protease (enzyme) part sits at the opposite end from the Gla domain, which acts as a targeting device.
- Warfarin
- it interferes with the vitamin K step, so fewer working Gla residues are made.
Exam traps
- Calcium does bind to Gla domains, but the calcium bridge goes to phospholipid on activated platelets, not to collagen.
- Gla residues are not enzymes and do not turn fibrinogen into fibrin, because thrombin does that.
- Kringle domains (loop-shaped protein folds) lie between the Gla domain and the enzyme domain and do not give prothrombin its affinity for membranes; the Gla domain does.
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