Schultz et al. (1998) Proc. Natl. Acad. Sci. USA 95, 5857-5864
Letunic et al. (2012) Nucleic Acids Res , doi:10.1093/nar/gkr931

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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)
Family alignment:	View or CHROMA formatCLUSTALW formatMSF formatFASTA formatPIR format

There are 513 GLA domains in 512 proteins in SMART's nrdb database.

Click on the following links for more information.

• Evolution (species in which this domain is found)

• Click on to expand nodes. To display all proteins with a GLA domain in a specific node, click on it.

  This tree shows only several representative species. The complete taxonomic breakdown of all proteins with GLA domain is also avaliable.

  Useful shortcuts: Expand all nodes or Collapse tree
  Go to specific node: Homo sapiens, Mus musculus, Rattus norvegicus, Takifugu rubripes

• 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
  • Display abstract

  • 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
  • Display abstract

  • 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
  • Display abstract

  • 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
  Coagulation factor IXa heavy chain (P00740) (SMART)	OMIM:306900: Hemophilia B ; Warfarin sensitivity
  Activation peptide (P04070) (SMART)	OMIM:176860: Thrombophilia due to protein C deficiency ; Purpura fulminans, neonatal

• 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	Main view	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
  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

• Links (links to other resources describing this domain)

• INTERPRO	IPR000294
  PROSITE	GLA_DOMAIN

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