{PDOC00011}
{PS00011; GLA_1}
{PS50998; GLA_2}
{BEGIN}
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* Gamma-carboxyglutamic acid-rich (Gla) domain signature and profile *
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The  vitamin  K-dependent  blood  coagulation  factor  IX  as  well as several
extracellular  regulatory proteins require vitamin K for the posttranslational
synthesis  of  gamma-carboxyglutamic  acid,  an  amino  acid  clustered in the
N-terminal  Gla  domain  of these proteins [1,2]. The Gla domain is a membrane
binding  motif  which,  in  the  presence  of  calcium  ions,  interacts  with
phospholipid membranes that include phosphatidylserine.

The  3D  structure  of  the  Gla  domain  has  been  solved  (see  for example
<PDB:1CFH>)  [3,4].  Calcium  ions  induce  conformational  changes in the Gla
domain  and  are  necessary  for  the  Gla  domain  to fold properly. 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 [4].

Proteins known to contain a Gla domain are listed below:

 - A number of plasma proteins involved in blood coagulation.   These proteins
   are prothrombin, coagulation factors VII, IX and X, proteins C, S, and Z.
 - Two proteins that  occur  in calcified tissues:  osteocalcin (also known as
   bone-Gla protein, BGP), and matrix Gla-protein (MGP).
 - Proline-rich Gla proteins 1 and 2 [5].
 - Cone snail venom peptides: conantokin-G and -T, and conotoxin GS [6].

The  pattern  we  developed  start with the conserved Gla-x(3)-Gla-x-Cys motif
found  in  the  middle of the domain which seems to be important for substrate
recognition by the carboxylase [7] and end with the last conserved position of
the  domain (an aromatic residue). We also developed a profile that covers the
whole Gla domain.

-Consensus pattern: E-x(2)-[ERK]-E-x-C-x(6)-[EDR]-x(10,11)-[FYA]-[YW]
                    [The 2 E's are the carboxylation site]
-Sequences known to belong to this class detected by the pattern: ALL.
-Other sequence(s) detected in Swiss-Prot: 1.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.

-Note: All glutamic residues present in the domain are potential carboxylation
 sites; in coagulation proteins, all are modified to Gla, while in BGP and MGP
 some are not.

-Expert(s) to contact by email:
           Price P.A.; pprice@ucsd.edu

-Last update: June 2004 / Pattern and text revised; profile added.

[ 1] Friedman P.A., Przysiecki C.T.
     "Vitamin K-dependent carboxylation."
     Int. J. Biochem. 19:1-7(1987).
     PubMed=3106112
[ 2] Vermeer C.
     "Gamma-carboxyglutamate-containing proteins and the vitamin
     K-dependent carboxylase."
     Biochem. J. 266:625-636(1990).
     PubMed=2183788
[ 3] Freedman S.J., Furie B.C., Furie B., Baleja J.D.
     "Structure of the metal-free gamma-carboxyglutamic acid-rich membrane
     binding region of factor IX by two-dimensional NMR spectroscopy."
     J. Biol. Chem. 270:7980-7987(1995).
     PubMed=7713897
[ 4] Freedman S.J., Blostein M.D., Baleja J.D., Jacobs M., Furie B.C.,
     Furie B.
     "Identification of the phospholipid binding site in the vitamin
     K-dependent blood coagulation protein factor IX."
     J. Biol. Chem. 271:16227-16236(1996).
     PubMed=8663165
[ 5] Kulman J.D., Harris J.E., Haldeman B.A., Davie E.W.
     "Primary structure and tissue distribution of two novel proline-rich
     gamma-carboxyglutamic acid proteins."
     Proc. Natl. Acad. Sci. U.S.A. 94:9058-9062(1997).
     PubMed=9256434
[ 6] Haack J.A., Rivier J.E., Parks T.N., Mena E.E., Cruz L.J., Olivera B.M.
     "Conantokin-T. A gamma-carboxyglutamate containing peptide with
     N-methyl-d-aspartate antagonist activity."
     J. Biol. Chem. 265:6025-6029(1990).
     PubMed=2180939
[ 7] Price P.A., Fraser J.D., Metz-Virca G.
     "Molecular cloning of matrix Gla protein: implications for substrate
     recognition by the vitamin K-dependent gamma-carboxylase."
     Proc. Natl. Acad. Sci. U.S.A. 84:8335-8339(1987).
     PubMed=3317405

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