P38435 (VKGC_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Vitamin K-dependent gamma-carboxylase
EC=4.1.1.90

Alternative name(s):
Gamma-glutamyl carboxylase
Peptidyl-glutamate 4-carboxylase
Vitamin K gamma glutamyl carboxylase

Gene names

Name:	GGCX
Synonyms:	GC

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	758 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Mediates the vitamin K-dependent carboxylation of glutamate residues to calcium-binding gamma-carboxyglutamate (Gla) residues with the concomitant conversion of the reduced hydroquinone form of vitamin K to vitamin K epoxide. Ref.10
Catalytic activity	[Peptidyl]-4-carboxyglutamate + 2,3-epoxyphylloquinone + H2O = [peptidyl]-glutamate + CO2 + O2 + phylloquinone.
Subunit structure	Monomer. May interact with CALU By similarity.
Subcellular location	Endoplasmic reticulum membrane; Multi-pass membrane protein Ref.6.
Involvement in disease	Defects in GGCX are a cause of combined deficiency of vitamin K-dependent clotting factors type 1 (VKCFD1) [MIM:277450]; also known as multiple coagulation factor deficiency III (MCFD3). VKCFD leads to a bleeding tendency that is usually reversed by oral administration of vitamin K. Ref.13 Ref.14 Ref.15 Ref.16 Defects in GGCX are the cause of pseudoxanthoma elasticum-like disorder with multiple coagulation factor deficiency (PXEL-MCFD) [MIM:610842]. This syndrome is characterized by hyperlaxity of the skin involving the entire body. Important phenotypic differences with classical PXE include much more severe skin laxity with spreading toward the trunk and limbs with thick, leathery skin folds rather than confinement to flexural areas, and no decrease in visual acuity. Moreover, detailed electron microscopic analyzes revealed that alterations of elastic fibers as well as their mineralization are slightly different from those in classic PXE. Ref.17
Miscellaneous	The vitamin K-dependent protein substrates of carboxylase have usually a propeptide that binds to a high-affinity site on the carboxylase. CO2, O2 and reduced vitamin K are cosubstrates.
Sequence similarities	Belongs to the vitamin K-dependent gamma-carboxylase family.
Biophysicochemical properties	pH dependence: Optimum pH is 7.

Ontologies

Keywords
Cellular component	Endoplasmic reticulum Membrane
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Domain	Transmembrane Transmembrane helix
Molecular function	Lyase
PTM	Acetylation Disulfide bond Glycoprotein Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	blood coagulation Traceable author statement. Source: ProtInc peptidyl-glutamic acid carboxylation Traceable author statement. Source: Reactome post-translational protein modification Traceable author statement. Source: Reactome
Cellular component	endoplasmic reticulum membrane Traceable author statement. Source: Reactome integral to membrane Traceable author statement. Source: ProtInc membrane fraction Traceable author statement. Source: ProtInc
Molecular function	gamma-glutamyl carboxylase activity Traceable author statement. Source: ProtInc
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Initiator methionine	1	1	Removed
	Chain	2 – 758	757	Vitamin K-dependent gamma-carboxylase		PRO_0000191823
Regions
	Topological domain	2 – 60	59	Cytoplasmic Potential
	Transmembrane	61 – 81	21	Helical; Potential
	Topological domain	82 – 113	32	Lumenal Potential
	Transmembrane	114 – 134	21	Helical; Potential
	Topological domain	135 – 136	2	Cytoplasmic Potential
	Transmembrane	137 – 157	21	Helical; Potential
	Topological domain	158 – 292	135	Lumenal Potential
	Transmembrane	293 – 313	21	Helical; Potential
	Topological domain	314 – 361	48	Cytoplasmic Potential
	Transmembrane	362 – 382	21	Helical; Potential
	Topological domain	383 – 758	376	Lumenal Potential
Sites
	Active site	218	1	Proton acceptor Ref.10
Amino acid modifications
	Modified residue	2	1	N-acetylalanine Ref.11
	Modified residue	11	1	Phosphoserine Ref.11
	Glycosylation	459	1	N-linked (GlcNAc...) Ref.12
	Glycosylation	550	1	N-linked (GlcNAc...) Ref.12
	Disulfide bond	99 ↔ 450		Ref.8
Natural variations
	Natural variant	299	1	F → S in PXEL-MCFD. Ref.17		VAR_032979
	Natural variant	325	1	R → Q. Ref.1 Corresponds to variant rs699664 [ dbSNP | Ensembl ].		VAR_005780
	Natural variant	394	1	L → R in VKCFD1; affects glutamate binding. Ref.13 Ref.15		VAR_005781
	Natural variant	476	1	R → C in PXEL-MCFD. Ref.17		VAR_032980
	Natural variant	476	1	R → H in PXEL-MCFD. Ref.17		VAR_032981
	Natural variant	485	1	R → P in VKCFD1. Ref.16		VAR_021826
	Natural variant	493	1	W → S in PXEL-MCFD. Ref.17		VAR_032982
	Natural variant	501	1	W → S in VKCFD1. Ref.14 Corresponds to variant rs28928872 [ dbSNP | Ensembl ].		VAR_015218
	Natural variant	558	1	G → R in PXEL-MCFD. Ref.17		VAR_032983
Experimental info
	Mutagenesis	160	1	H → A: No effect on activity. Ref.10
	Mutagenesis	218	1	K → A: No activity. Ref.10
	Mutagenesis	287	1	H → A: No effect on activity. Ref.10
	Mutagenesis	381	1	H → A: No effect on activity. Ref.10
	Sequence conflict	400	1	D → N in AAA91834. Ref.3

Sequences

	Sequence		Length	Mass (Da)
	P38435 [UniParc]. Last modified December 20, 2005. Version 2. Checksum: 720D5B08E9B558C8	FASTA	758	87,561
	10 20 30 40 50 60 MAVSAGSART SPSSDKVQKD KAELISGPRQ DSRIGKLLGF EWTDLSSWRR LVTLLNRPTD 70 80 90 100 110 120 PASLAVFRFL FGFLMVLDIP QERGLSSLDR KYLDGLDVCR FPLLDALRPL PLDWMYLVYT 130 140 150 160 170 180 IMFLGALGMM LGLCYRISCV LFLLPYWYVF LLDKTSWNNH SYLYGLLAFQ LTFMDANHYW 190 200 210 220 230 240 SVDGLLNAHR RNAHVPLWNY AVLRGQIFIV YFIAGVKKLD ADWVEGYSME YLSRHWLFSP 250 260 270 280 290 300 FKLLLSEELT SLLVVHWGGL LLDLSAGFLL FFDVSRSIGL FFVSYFHCMN SQLFSIGMFS 310 320 330 340 350 360 YVMLASSPLF CSPEWPRKLV SYCPRRLQQL LPLKAAPQPS VSCVYKRSRG KSGQKPGLRH 370 380 390 400 410 420 QLGAAFTLLY LLEQLFLPYS HFLTQGYNNW TNGLYGYSWD MMVHSRSHQH VKITYRDGRT 430 440 450 460 470 480 GELGYLNPGV FTQSRRWKDH ADMLKQYATC LSRLLPKYNV TEPQIYFDIW VSINDRFQQR 490 500 510 520 530 540 IFDPRVDIVQ AAWSPFQRTS WVQPLLMDLS PWRAKLQEIK SSLDNHTEVV FIADFPGLHL 550 560 570 580 590 600 ENFVSEDLGN TSIQLLQGEV TVELVAEQKN QTLREGEKMQ LPAGEYHKVY TTSPSPSCYM 610 620 630 640 650 660 YVYVNTTELA LEQDLAYLQE LKEKVENGSE TGPLPPELQP LLEGEVKGGP EPTPLVQTFL 670 680 690 700 710 720 RRQQRLQEIE RRRNTPFHER FFRFLLRKLY VFRRSFLMTC ISLRNLILGR PSLEQLAQEV 730 740 750 TYANLRPFEA VGELNPSNTD SSHSNPPESN PDPVHSEF

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and expression of the cDNA for human gamma-glutamyl carboxylase." Wu S.-M., Cheung W.-F., Frazier D., Stafford D.W. Science 254:1634-1636(1991) [PubMed: 1749935] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT GLN-325.
[2]	"Genomic sequence and transcription start site for the human gamma-glutamyl carboxylase." Wu S.-M., Stafford D.W., Frazier L.D., Fu Y.Y., High K.A., Chu K., Sanchez-Vega B., Solera J. Blood 89:4058-4062(1997) [PubMed: 9166845] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	Ying L., Lipsky J.J. Submitted (MAR-1996) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[4]	"Generation and annotation of the DNA sequences of human chromosomes 2 and 4." Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H. , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K. Nature 434:724-731(2005) [PubMed: 15815621] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain.
[6]	"A topological study of the human gamma-glutamyl carboxylase." Tie J., Wu S.-M., Jin D., Nicchitta C.V., Stafford D.W. Blood 96:973-978(2000) [PubMed: 10910912] [Abstract] Cited for: SUBCELLULAR LOCATION, TOPOLOGY.
[7]	"A novel fluorescence assay to study propeptide interaction with gamma-glutamyl carboxylase." Presnell S.R., Tripathy A., Lentz B.R., Jin D.Y., Stafford D.W. Biochemistry 40:11723-11733(2001) [PubMed: 11570873] [Abstract] Cited for: PROPEPTIDE INTERACTION, MONOMER.
[8]	"Determination of disulfide bond assignment of human vitamin K-dependent gamma-glutamyl carboxylase by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry." Tie J.K., Mutucumarana V.P., Straight D.L., Carrick K.L., Pope R.M., Stafford D.W. J. Biol. Chem. 278:45468-45475(2003) [PubMed: 12963724] [Abstract] Cited for: DISULFIDE BOND.
[9]	"The vitamin K-dependent carboxylase." Berkner K.L. Annu. Rev. Nutr. 25:127-149(2005) [PubMed: 16011462] [Abstract] Cited for: REVIEW.
[10]	"Bronsted analysis reveals Lys218 as the carboxylase active site base that deprotonates vitamin K hydroquinone to initiate vitamin K-dependent protein carboxylation." Rishavy M.A., Hallgren K.W., Yakubenko A.V., Shtofman R.L., Runge K.W., Berkner K.L. Biochemistry 45:13239-13248(2006) [PubMed: 17073445] [Abstract] Cited for: MUTAGENESIS OF HIS-160; LYS-218; HIS-287 AND HIS-381, ACTIVE SITE, FUNCTION, PH DEPENDENCE, REACTION MECHANISM.
[11]	"Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach." Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S. Anal. Chem. 81:4493-4501(2009) [PubMed: 19413330] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-11, MASS SPECTROMETRY. Tissue: Embryonic kidney.
[12]	"Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry." Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H. J. Proteome Res. 8:651-661(2009) [PubMed: 19159218] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-459 AND ASN-550, MASS SPECTROMETRY. Tissue: Liver.
[13]	"A missense mutation in gamma-glutamyl carboxylase gene causes combined deficiency of all vitamin K-dependent blood coagulation factors." Brenner B., Sanchez-Vega B., Wu S.M., Lanir N., Stafford D.W., Solera J. Blood 92:4554-4559(1998) [PubMed: 9845520] [Abstract] Cited for: VARIANT VKCFD1 ARG-394.
[14]	"Novel mutation in the gamma-glutamyl carboxylase gene resulting in congenital combined deficiency of all vitamin K-dependent blood coagulation factors." Spronk H.M.H., Farah R.A., Buchanan G.R., Vermeer C., Soute B.A.M. Blood 96:3650-3652(2000) [PubMed: 11071668] [Abstract] Cited for: VARIANT VKCFD1 SER-501.
[15]	"Expression and characterization of the naturally occurring mutation L394R in human gamma-glutamyl carboxylase." Mutucumarana V.P., Stafford D.W., Stanley T.B., Jin D.-Y., Solera J., Brenner B., Azerad R., Wu S.-M. J. Biol. Chem. 275:32572-32577(2000) [PubMed: 10934213] [Abstract] Cited for: CHARACTERIZATION OF VARIANT VKCFD1 ARG-394.
[16]	"Compound heterozygous mutations in the gamma-glutamyl carboxylase gene cause combined deficiency of all vitamin K-dependent blood coagulation factors." Rost S., Fregin A., Koch D., Compes M., Mueller C.R., Oldenburg J. Br. J. Haematol. 126:546-549(2004) [PubMed: 15287948] [Abstract] Cited for: VARIANT VKCFD1 PRO-485.
[17]	"Pseudoxanthoma elasticum-like phenotype with cutis laxa and multiple coagulation factor deficiency represents a separate genetic entity." Vanakker O.M., Martin L., Gheduzzi D., Leroy B.P., Loeys B.L., Guerci V.I., Matthys D., Terry S.F., Coucke P.J., Pasquali-Ronchetti I., De Paepe A. J. Invest. Dermatol. 127:581-587(2007) [PubMed: 17110937] [Abstract] Cited for: VARIANTS PXEL-MCFD SER-299; CYS-476; HIS-476; SER-493 AND ARG-558.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	M81592 mRNA. Translation: AAA58643.1. U65896 Genomic DNA. Translation: AAB39832.1. L17128 mRNA. Translation: AAA91834.1. AC016753 Genomic DNA. Translation: AAY24340.1. BC013979 mRNA. Translation: AAH13979.1.
IPI	IPI00305698.
PIR	A39283.
RefSeq	NP_000812.2. NM_000821.5. NP_001135741.1. NM_001142269.2.
UniGene	Hs.592466. Hs.77719.
3D structure databases
ProteinModelPortal	P38435.
ModBase	Search...
Protein-protein interaction databases
STRING	P38435.
PTM databases
PhosphoSite	P38435.
Polymorphism databases
DMDM	84028279.
Proteomic databases
PRIDE	P38435.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000233838; ENSP00000233838; ENSG00000115486.
GeneID	2677.
KEGG	hsa:2677.
UCSC	uc002sps.1. human.
Organism-specific databases
CTD	2677.
GeneCards	GC02M085774.
H-InvDB	HIX0002220.
HGNC	HGNC:4247. GGCX.
HPA	HPA018284.
MIM	137167. gene. 277450. phenotype. 610842. phenotype.
neXtProt	NX_P38435.
Orphanet	91135. Body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency. 98434. Hereditary combined deficiency of vitamin K-dependent clotting factors.
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG09125.
HOGENOM	HBG443667.
HOVERGEN	HBG012798.
InParanoid	P38435.
OMA	YKRSRAK.
OrthoDB	EOG4KH2TJ.
PhylomeDB	P38435.
Enzyme and pathway databases
BioCyc	MetaCyc:ENSG00000115486-MONOMER.
Reactome	REACT_17015. Metabolism of proteins.
Gene expression databases
ArrayExpress	P38435.
Bgee	P38435.
CleanEx	HS_GC. HS_GGCX.
Genevestigator	P38435.
GermOnline	ENSG00000115486. Homo sapiens.
Family and domain databases
InterPro	IPR011051. Cupin_RmlC_type. IPR011020. HTTM. IPR014710. RmlC-like_jellyroll. IPR007782. VKG_COase. [Graphical view]
Gene3D	G3DSA:2.60.120.10. RmlC-like_jellyroll. 1 hit.
KO	K10106.
PANTHER	PTHR12639. VKG_carbox. 1 hit.
Pfam	PF05090. VKG_Carbox. 1 hit. [Graphical view]
SMART	SM00752. HTTM. 1 hit. [Graphical view]
SUPFAM	SSF51182. RmlC_like_cupin. 1 hit.
ProtoNet	Search...
Other
DrugBank	DB01125. Anisindione. DB00100. Coagulation Factor IX. DB00036. Coagulation factor VIIa. DB00055. Drotrecogin alfa. DB00142. L-Glutamic Acid. DB00170. Menadione. DB01022. Phytonadione.
NextBio	10570.
SOURCE	Search...

Entry information

Entry name

VKGC_HUMAN

Accession

Primary (citable) accession number: P38435
Secondary accession number(s): Q14415, Q6GU45

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1994
Last sequence update:	December 20, 2005
Last modified:	January 25, 2012
This is version 110 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.