GLA

Domain containing Gla (gamma-carboxyglutamate) residues.

• SMART accession number: SM00069
• Description: A hyaluronan-binding domain found in proteins associated with the extracellular matrix, cell adhesion and cell migration.
• Interpro abstract (IPR000294):

  The GLA (gamma-carboxyglutamic acid-rich) domain contains glutamate residues that have been post-translationally modified by vitamin K-dependent carboxylation to form gamma-carboxyglutamate (Gla) [ (PUBMED:18374189) (PUBMED:11818531) (PUBMED:18374194) ]. All glutamic acid (Glu) residues present in the GLA domain are potential carboxylation sites; in coagulation proteins, all Gu residues are modified to Gla, while in osteocalcin and matrix Gla proteins only some Glu residues are modified to Gla.

  The GLA domain is responsible for the high-affinity binding of calcium ions. It starts at the N-terminal extremity of the mature form of proteins and ends with a conserved aromatic residue; a conserved Gla-x(3)-Gla-x-Cys motif [ (PUBMED:3317405) ] is found in the middle of the domain which seems to be important for substrate recognition by the carboxylase.

  The 3D structure of the GLA domain has been solved [ (PUBMED:7713897) (PUBMED:8663165) ]. Calcium ions induce conformational changes in the GLA domain that and are necessary for the proper folding of the GLA domain. A common structural feature of functional GLA domains is the clustering of N-terminal hydrophobic residues into a hydrophobic patch that mediates interaction with the cell surface membrane [ (PUBMED:8663165) ].

  Proteins known to contain a GLA domain include [ (PUBMED:18373251) ]:

  • Coagulation factor X [ (PUBMED:17723139) ]
  • Coagulation factor VII [ (PUBMED:18642129) ]
  • Coagulation factor IX [ (PUBMED:18680528) ]
  • Coagulation factor XIV (vitamin K-dependent protein C) [ (PUBMED:16156662) ]
  • Vitamin K-dependent protein S [ (PUBMED:16460467) ]
  • Vitamin K-dependent protein Z [ (PUBMED:2403355) ]
  • Prothrombin
  • Transthyretin
  • Osteocalcin (also known as bone-Gla protein, BGP)
  • Matrix Gla protein (MGP) [ (PUBMED:18369157) ]
  • Inter-alpha-trypsin inhibitor heavy chain H2
  • Growth arrest-specific protein 6 (Gas-6) [ (PUBMED:9163328) ]

• GO component: extracellular region (GO:0005576)
• GO function: calcium ion binding (GO:0005509)

There are 4471 GLA domains in 4427 proteins in SMART's nrdb database.

Literature (relevant references for this domain)

Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

• Parkar AA, Day AJ
• Overlapping sites on the Link module of human TSG-6 mediate binding to hyaluronan and chrondroitin-4-sulphate.
• FEBS Lett. 1997; 410: 413-7

Link modules are hyaluronan-binding domains that are involved in the formation and stability of extracellular matrix and cell migration. We have examined the glycosaminoglycan specificity of the Link module from the arthritis-associated protein, human TSG-6, by microtitre plate-based assays employing biotinylated-hyaluronan or mono-biotinylated Link module. This domain was found to interact specifically with chondroitin-4-sulphate (C4S), with similar affinity to hyaluronan, but not with chondroitin-6-sulphate or heparin. Competition experiments indicate that C4S and hyaluronan have overlapping binding surfaces on the TSG-6 Link module. Disease-associated changes in C4S expression may influence the localisation and biological role of TSG-6.

• Brissett NC, Perkins SJ
• The protein fold of the hyaluronate-binding proteoglycan tandem repeat domain of link protein, aggrecan and CD44 is similar to that of the C-type lectin superfamily.
• FEBS Lett. 1996; 388: 211-6

Link protein and aggrecan of the extracellular matrix each contain two proteoglycan tandem repeat (PTR) domains that interact with hyaluronate. Consensus secondary structure predictions for 59 PTR sequences and 129 C-type lectin sequences give similar patterns of two alpha-helices and up to seven beta-strands. Protein fold recognition analyses show that the 59 PTR sequences are highly compatible with the C-type lectin crystal structure. The predicted fold consists of a conserved motif formed from an antiparallel beta-sheet flanked by two alpha-helices, the motif being attached to two distinct types of beta-sheet region in the two superfamilies. Arg9 or Lys11 on an exposed loop and up to three other Arg residues in the beta-sheet region are conserved and may form part of a hyaluronate binding site.

• Kohda D et al.
• Solution structure of the link module: a hyaluronan-binding domain involved in extracellular matrix stability and cell migration.
• Cell. 1996; 86: 767-75

Link modules are hyaluronan-binding domains found in proteins involved in the assembly of extracellular matrix, cell adhesion, and migration. The solution structure of the Link module from human TSG-6 was determined and found to consist of two alpha helices and two antiparallel beta sheets arranged around a large hydrophobic core. This defines the consensus fold for the Link module superfamily, which includes CD44, cartilage link protein, and aggrecan. The TSG-6 Link module was shown to interact with hyaluronan, and a putative binding surface was identified on the structure. A structural database search revealed close similarity between the Link module and the C-type lectin domain, with the predicted hyaluronan-binding site at an analogous position to the carbohydrate-binding pocket in E-selectin.

Disease (disease genes where sequence variants are found in this domain)

SwissProt sequences and OMIM curated human diseases associated with missense mutations within the GLA domain.

Protein	Disease
Vitamin K-dependent protein C (P04070) (SMART)	OMIM:176860: Thrombophilia due to protein C deficiency ; Purpura fulminans, neonatal
Coagulation factor IX (P00740) (SMART)	OMIM:306900: Hemophilia B ; Warfarin sensitivity

Metabolism (metabolic pathways involving proteins which contain this domain)

% proteins involved	KEGG pathway ID	Description
70.97	map04610	Complement and coagulation cascades
14.52	map04810	Regulation of actin cytoskeleton
14.52	map04080	Neuroactive ligand-receptor interaction

This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with GLA domain which could be assigned to a KEGG orthologous group, and not all proteins containing GLA domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

Structure (3D structures containing this domain)

3D Structures of GLA domains in PDB

PDB code	Title
1cfh	STRUCTURE OF THE METAL-FREE GAMMA-CARBOXYGLUTAMIC ACID-RICH MEMBRANE BINDING REGION OF FACTOR IX BY TWO-DIMENSIONAL NMR SPECTROSCOPY
1cfi	NMR STRUCTURE OF CALCIUM ION-BOUND GAMMA-CARBOXY-GLUTAMIC ACID-RICH DOMAIN OF FACTOR IX
1dan	COMPLEX OF ACTIVE SITE INHIBITED HUMAN BLOOD COAGULATION FACTOR VIIA WITH HUMAN RECOMBINANT SOLUBLE TISSUE FACTOR
1ezq	CRYSTAL STRUCTURE OF HUMAN COAGULATION FACTOR XA COMPLEXED WITH RPR128515
1f0r	CRYSTAL STRUCTURE OF HUMAN COAGULATION FACTOR XA COMPLEXED WITH RPR208815
1f0s	Crystal Structure of Human Coagulation Factor XA Complexed with RPR208707
1fak	HUMAN TISSUE FACTOR COMPLEXED WITH COAGULATION FACTOR VIIA INHIBITED WITH A BPTI-MUTANT
1iod	CRYSTAL STRUCTURE OF THE COMPLEX BETWEEN THE COAGULATION FACTOR X BINDING PROTEIN FROM SNAKE VENOM AND THE GLA DOMAIN OF FACTOR X
1j34	Crystal Structure of Mg(II)-and Ca(II)-bound Gla Domain of Factor IX Complexed with Binding Protein
1j35	Crystal Structure of Ca(II)-bound Gla Domain of Factor IX Complexed with Binding Protein
1ksn	Crystal Structure of Human Coagulation Factor XA Complexed with FXV673
1lpg	CRYSTAL STRUCTURE OF FXA IN COMPLEX WITH 79.
1lpk	CRYSTAL STRUCTURE OF FXA IN COMPLEX WITH 125.
1lpz	CRYSTAL STRUCTURE OF FXA IN COMPLEX WITH 41.
1lqd	CRYSTAL STRUCTURE OF FXA IN COMPLEX WITH 45.
1lqv	Crystal structure of the Endothelial protein C receptor with phospholipid in the groove in complex with Gla domain of protein C.
1mgx	COAGULATION FACTOR, MG(II), NMR, 7 STRUCTURES (BACKBONE ATOMS ONLY)
1nfu	CRYSTAL STRUCTURE OF HUMAN COAGULATION FACTOR XA COMPLEXED WITH RPR132747
1nfw	CRYSTAL STRUCTURE OF HUMAN COAGULATION FACTOR XA COMPLEXED WITH RPR209685
1nfx	CRYSTAL STRUCTURE OF HUMAN COAGULATION FACTOR XA COMPLEXED WITH RPR208944
1nfy	CRYSTAL STRUCTURE OF HUMAN COAGULATION FACTOR XA COMPLEXED WITH RPR200095
1nl0	Crystal structure of human factor IX Gla domain in complex of an inhibitory antibody, 10C12
1nl1	BOVINE PROTHROMBIN FRAGMENT 1 IN COMPLEX WITH CALCIUM ION
1nl2	BOVINE PROTHROMBIN FRAGMENT 1 IN COMPLEX WITH CALCIUM AND LYSOPHOSPHOTIDYLSERINE
1o5d	Dissecting and Designing Inhibitor Selectivity Determinants at the S1 site Using an Artificial Ala190 Protease (Ala190 uPA)
1p0s	Crystal Structure of Blood Coagulation Factor Xa in Complex with Ecotin M84R
1pfx	PORCINE FACTOR IXA
1q3m	1H NMR structure bundle of bovine Ca2+-osteocalcin
1q8h	Crystal structure of porcine osteocalcin
1w0y	tf7a_3771 complex
1w2k	tf7a_4380 complex
1whe	COAGULATION FACTOR, NMR, 20 STRUCTURES
1whf	COAGULATION FACTOR, NMR, 15 STRUCTURES
1wqv	Human Factor Viia-Tissue Factor Complexed with propylsulfonamide-D-Thr-Met-p-aminobenzamidine
1wss	Human Factor Viia-Tissue Factor in Complex with peprid mimetic inhibitor that has two charge groups in P2 and P4
1wtg	Human Factor Viia-Tissue Factor Complexed with ethylsulfonamide-D-biphenylalanine-Gln-p-aminobenzamidine
1wun	Human Factor Viia-Tissue Factor Complexed with ethylsulfonamide-D-Trp-Gln-p-aminobenzamidine
1wv7	Human Factor Viia-Tissue Factor Complexed with ethylsulfonamide-D-5-propoxy-Trp-Gln-p-aminobenzamidine
1x7a	Porcine Factor IXa Complexed to 1-{3-[amino(imino)methyl]phenyl}-N-[4-(1H-benzimidazol-1-yl)-2-fluorophenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide
1z6j	Crystal Structure of a ternary complex of Factor VIIa/Tissue Factor/Pyrazinone Inhibitor
2a2q	Complex of Active-site Inhibited Human Coagulation Factor VIIa with Human Soluble Tissue Factor in the Presence of Ca2+, Mg2+, Na+, and Zn2+
2aei	Crystal structure of a ternary complex of factor VIIa/tissue factor and 2-[[6-[3-(aminoiminomethyl)phenoxy]-3,5-difluro-4-[(1-methyl-3-phenylpropyl)amino]-2-pyridinyl]oxy]-benzoic acid
2aer	Crystal Structure of Benzamidine-Factor VIIa/Soluble Tissue Factor complex.
2b7d	Factor VIIa Inhibitors: Chemical Optimization, Preclinical Pharmacokinetics, Pharmacodynamics, and Efficacy in a Baboon Thrombosis Model
2b8o	Crystal Structure of Glu-Gly-Arg-Chloromethyl Ketone-Factor VIIa/Soluble Tissue Factor Complex
2boh	Crystal structure of factor Xa in complex with compound ""1""
2c4f	crystal structure of factor VII.stf complexed with pd0297121
2cji	Crystal structure of a Human Factor Xa inhibitor complex
2ec9	Crystal structure analysis of human Factor VIIa , Souluble tissue factor complexed with BCX-3607
2f9b	Discovery of Novel Heterocyclic Factor VIIa Inhibitors
2fir	Crystal structure of DFPR-VIIa/sTF
2flb	Discovery of a Novel Hydroxy Pyrazole Based Factor IXa Inhibitor
2flr	Novel 5-Azaindole Factor VIIa Inhibitors
2j2u	CRYSTAL STRUCTURE OF A HUMAN FACTOR XA INHIBITOR COMPLEX
2j34	CRYSTAL STRUCTURE OF A HUMAN FACTOR XA INHIBITOR COMPLEX
2j38	CRYSTAL STRUCTURE OF A HUMAN FACTOR XA INHIBITOR COMPLEX
2j4i	CRYSTAL STRUCTURE OF A HUMAN FACTOR XA INHIBITOR COMPLEX
2j94	CRYSTAL STRUCTURE OF A HUMAN FACTOR XA INHIBITOR COMPLEX
2j95	CRYSTAL STRUCTURE OF A HUMAN FACTOR XA INHIBITOR COMPLEX
2pf1	STRUCTURE OF BOVINE PROTHROMBIN FRAGMENT 1 REFINED AT 2.25 ANGSTROMS RESOLUTION
2pf2	THE CA+2 ION AND MEMBRANE BINDING STRUCTURE OF THE GLA DOMAIN OF CA-PROTHROMBIN FRAGMENT 1
2spt	DIFFERENCES IN THE METAL ION STRUCTURE BETWEEN SR-AND CA-PROTHROMBIN FRAGMENT 1
2uwl	Selective and Dual Action Orally Active Inhibitors of Thrombin and Factor Xa
2uwo	Selective and Dual Action Orally Active Inhibitors of Thrombin and Factor Xa
2uwp	Factor Xa inhibitor complex
2vh0	Structure and property based design of factor Xa inhibitors:biaryl pyrrolidin-2-ones incorporating basic heterocyclic motifs
2vh6	Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with biaryl P4 motifs
2wyg	Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with monoaryl P4 motifs
2wyj	Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with monoaryl P4 motifs
2y7x	The discovery of potent and long-acting oral factor Xa inhibitors with tetrahydroisoquinoline and benzazepine P4 motifs
2y7z	Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with aminoindane and phenylpyrrolidine P4 motifs
2y80	Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with aminoindane and phenylpyrrolidine P4 motifs
2y81	Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with aminoindane and phenylpyrrolidine P4 motifs
2y82	Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with aminoindane and phenylpyrrolidine P4 motifs
2yi8	Structure of the RNA polymerase VP1 from Infectious Pancreatic Necrosis Virus
2yi9	Structure of the RNA polymerase VP1 from Infectious Pancreatic Necrosis Virus in complex with magnesium
2yia	Structure of the RNA polymerase VP1 from Infectious Pancreatic Necrosis Virus
2yib	Structure of the RNA polymerase VP1 from Infectious Pancreatic Necrosis Virus
2zp0	Human factor viia-tissue factor complexed with benzylsulfonamide-D-ile-gln-P-aminobenzamidine
2zwl	Human factor viia-tissue factor complexed with highly selective peptide inhibitor
2zzu	Human Factor VIIA-Tissue Factor Complexed with ethylsulfonamide-D-5-(3-carboxybenzyloxy)-Trp-Gln-p-aminobenzamidine
3ela	Crystal structure of active site inhibited coagulation factor VIIA mutant in complex with soluble tissue factor
3jtc	Importance of Mg2+ in the Ca2+-Dependent Folding of the gamma-Carboxyglutamic Acid Domains of Vitamin K-Dependent clotting and anticlotting Proteins
3th2	Mg2+ Is Required for Optimal Folding of the Gamma-Carboxyglutamic Acid (Gla) Domains of Vitamin K-Dependent Clotting Factors At Physiological Ca2+
3th3	Mg2+ Is Required for Optimal Folding of the Gamma-Carboxyglutamic Acid (Gla) Domains of Vitamin K-Dependent Clotting Factors At Physiological Ca2+
3th4	Mg2+ Is Required for Optimal Folding of the Gamma-Carboxyglutamic Acid (Gla) Domains of Vitamin K-Dependent Clotting Factors At Physiological Ca2+
3zed	X-ray structure of the birnavirus VP1-VP3 complex
4bxs	Crystal Structure of the Prothrombinase Complex from the Venom of Pseudonaja Textilis
4bxw	Crystal Structure of the Prothrombinase Complex from the Venom of Pseudonaja Textilis
4ibl	Rubidium Sites in Blood Coagulation Factor VIIa
4mzz	Crystal structure of Bovine 3 Glu-Osteocalcin.
4nzq	Crystal structure of Ca2+-free prothrombin deletion mutant residues 146-167
4o03	Crystal structure of Ca2+ bound prothrombin deletion mutant residues 146-167
4y6d	4Y6D
4y71	4Y71
4y76	4Y76
4y79	4Y79
4y7a	4Y7A
4y7b	4Y7B
4ylq	4YLQ
4zh8	4ZH8
4zha	4ZHA
4zma	4ZMA
5edk	5EDK
5edm	5EDM

Links (links to other resources describing this domain)

• PROSITE: GLA_DOMAIN
• INTERPRO: IPR000294