GLA-domain is a protein domain that contains post-translational modifications of many glutamate residues by vitamin K-dependent carboxylation to form gamma-carboxyglutamate (Gla). The Gla residues are responsible for the high-affinity binding of calcium ions
GLA proteins
Some proteins with GLA-Domain
The following human Gla-containing proteins have been characterized to the level of primary structure:
Gla-proteins are known to occur in a wide variety of vertebrates: mammals, birds, reptiles, and fish.
- The venom of a number of Australian snakes acts by activating the human blood clotting system by snake Gla-containing enzymes that bind to the endothelium of human blood vessels
- the fish-hunting snail Conus geographus produces a venom containing hundreds of neuro-active peptides, or conotoxins, which is sufficiently toxic to kill an adult human. Several of the conotoxins contain 2-5 Gla residues.
Vitamin K-dependent crosstalk
Activated protein C (APC), a vitamin K-dependent plasma protein, plays a critical anticoagulant role in vivo by inactivating procoagulant factor Va (FVa) and factor VIIIa (FVIIIa), and thus down regulating thrombin (f2) generation. The endothelial protein C receptor (EPCR)-dependent cleavage of protease activated receptor 1 (PAR-1) by either APC or thrombin in lipid rafts initiates protective signaling responses in endothelial cells. The lipid raft localization renders the scissile bond of the PAR-1 exodomain unavailable for interaction with coagulation proteases. The binding of either the Gla-domain of protein C to EPCR or exosite-1 of thrombin to the C-terminal hirudin-like sequence of PAR-1 changes the membrane localization and/or the conformation of the PAR-1 exodomain to facilitate its recognition and subsequent cleavage by these proteases.
The vitamin K-dependent protein matrix Gla-protein (mgp) has been identified as a potent inhibitor of the transformation of smooth muscle cells in the vessel wall to osteoblast-like cells in a process known to precede arterial calcification. Growth arrest-specific gene 6 (gas6), which is similar to the anticoagulant protein S, has growth factor-like properties through its interaction with receptor tyrosine kinases of the TAM family. It has been shown to affects vascular smooth muscle cell apoptosis and movement.
Gla-Domain and membrane binding to lysophosphatidylserine molecule
PT1 is shown bound to one leaflet of a phospholipid bilayer composed of phosphatidylcholine with a single lysophosphatidylserine molecule (shown as a stick model). The head group of the lysophosphatidylserine is bound to PT1 as in our crystal structure but the acyl chain of the lysophosphatidylserine is elongated and inserted into the lipid bilayer. The residues of the Gla domain 'hydrophobic patch' of Ca2+-liganded PT1 are inserted into the interstitial region of the lipid bilayer. PT1 is shown in a space-filling model with residues of the omega-loop in yellow, the side chain nitrogens of Lys3, Arg10 and Arg16 in blue and Ca2+ ions in black. Lysophosphatidylserine: carbon, teal; oxygen, red; nitrogen, blue; phosphorous, green.
Crystal structure of human sex hormone-binding globulin: steroid transport by a laminin G-like domain Similarity to GAS6 and protein S
