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Q14397 (GCKR_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 114. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Glucokinase regulatory protein

Short name=GKRP
Short name=Glucokinase regulator
Gene names
Name:GCKR
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length625 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Inhibits glucokinase (GCK) by forming an inactive complex with this enzyme. The affinity of GCKR for GCK is modulated by fructose metabolites: GCKR with bound fructose 6-phosphate has increased affinity for GCK, while GCKR with bound fructose 1-phosphate has strongly decreased affinity for GCK and does not inhibit GCK activity. Ref.10 Ref.11

Subunit structure

Interacts (fructose 6-phosphate bound form) with GCK. Ref.7 Ref.10 Ref.11

Subcellular location

Cytoplasm. Nucleus. Note: Under low glucose concentrations, GKRP associates with GCK and the inactive complex is recruited to the hepatocyte nucleus. Ref.7

Tissue specificity

Found in liver and pancreas. Not detected in muscle, brain, heart, thymus, intestine, uterus, adipose tissue, kidney, adrenal, lung or spleen. Ref.2 Ref.9

Domain

Fructose 1-phosphate and fructose 6-phosphate compete for the same binding site.

Polymorphism

Genetic variations in GCKR define the fasting plasma glucose levels quantitative trait locus 5 (FGQTL5) [MIM:613463]. The normal fasting plasma glucose level is defined as less than 100 mg glucose per deciliter plasma (5.55 mmol per liter). Higher fasting plasma glucose levels predict type 2 diabetes in young adults and increases the risk of mortality.

Sequence similarities

Belongs to the GCKR family.

Contains 2 SIS domains.

Ontologies

Keywords
   Biological processCarbohydrate metabolism
   Cellular componentCytoplasm
Nucleus
   Coding sequence diversityAlternative splicing
Polymorphism
   DomainRepeat
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcarbohydrate metabolic process

Traceable author statement. Source: Reactome

cellular glucose homeostasis

Inferred from electronic annotation. Source: Ensembl

glucose transport

Traceable author statement. Source: Reactome

hexose transport

Traceable author statement. Source: Reactome

negative regulation of glucokinase activity

Inferred from direct assay Ref.11. Source: UniProtKB

positive regulation of glucokinase activity

Inferred from electronic annotation. Source: Ensembl

protein import into nucleus, translocation

Inferred from sequence or structural similarity. Source: BHF-UCL

regulation of glucose transport

Traceable author statement. Source: Reactome

response to fructose

Inferred from direct assay PubMed 14627435. Source: BHF-UCL

small molecule metabolic process

Traceable author statement. Source: Reactome

transmembrane transport

Traceable author statement. Source: Reactome

triglyceride homeostasis

Inferred from mutant phenotype PubMed 19526250PubMed 20668700. Source: BHF-UCL

urate metabolic process

Inferred from mutant phenotype PubMed 19503597. Source: BHF-UCL

   Cellular_componentcytoplasm

Inferred from sequence or structural similarity. Source: UniProtKB

cytosol

Traceable author statement. Source: Reactome

mitochondrion

Inferred from electronic annotation. Source: Ensembl

nucleoplasm

Inferred from sequence or structural similarity. Source: UniProtKB

   Molecular_functioncarbohydrate binding

Inferred from electronic annotation. Source: Ensembl

enzyme inhibitor activity

Inferred from electronic annotation. Source: Ensembl

fructose-6-phosphate binding

Inferred from direct assay Ref.11. Source: UniProtKB

protein binding

Inferred from physical interaction PubMed 11522786. Source: IntAct

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

GCKP355572EBI-709948,EBI-709928

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q14397-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: Q14397-2)

The sequence of this isoform differs from the canonical sequence as follows:
     144-150: SVVASRE → WLPGRRE
     151-625: Missing.
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 625625Glucokinase regulatory protein
PRO_0000214826

Regions

Domain90 – 286197SIS 1
Domain320 – 499180SIS 2
Region109 – 1102Fructose 1-phosphate/Fructose 6-phosphate binding
Region179 – 1813Fructose 1-phosphate/Fructose 6-phosphate binding
Region199 – 2002Important for interaction with GCK By similarity
Region463 – 4653Essential for interaction with GCK

Sites

Binding site1531Fructose 1-phosphate
Binding site3481Fructose 1-phosphate
Binding site5141Fructose 1-phosphate/Fructose 6-phosphate

Natural variations

Alternative sequence144 – 1507SVVASRE → WLPGRRE in isoform 2.
VSP_054853
Alternative sequence151 – 625475Missing in isoform 2.
VSP_054854
Natural variant771E → G. Ref.3
Corresponds to variant rs8179206 [ dbSNP | Ensembl ].
VAR_018849
Natural variant2561G → S. Ref.3
Corresponds to variant rs8179212 [ dbSNP | Ensembl ].
VAR_018850
Natural variant4461P → L Associated with high triglyceride levels and low fasting plasma glucose levels; associated with a reduced risk for type 2 diabetes; the mutant protein is less efficiently regulated by physiological concentrations of fructose-6 phosphate. Ref.3 Ref.5 Ref.8 Ref.9 Ref.12
Corresponds to variant rs1260326 [ dbSNP | Ensembl ].
VAR_008906
Natural variant5401R → Q. Ref.3
Corresponds to variant rs8179249 [ dbSNP | Ensembl ].
VAR_018851

Experimental info

Mutagenesis326 – 3272KK → TT: No effect on inhibition of glucokinase. Ref.11
Mutagenesis4131D → A: Impairs inhibition of glucokinase. Ref.10 Ref.11
Mutagenesis450 – 4512KK → TT: Impairs inhibition of glucokinase. Ref.11
Mutagenesis463 – 4653LLF → ALA: Abolishes interaction with GCK. Abolishes inhibition of GCK. Ref.10 Ref.11
Sequence conflict2511P → V in CAB61828. Ref.2
Sequence conflict3931L → P in CAA88367. Ref.1
Sequence conflict5601H → R in CAA88367. Ref.1

Secondary structure

................................................................................................ 625
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified April 5, 2011. Version 6.
Checksum: DE750462AC603C80

FASTA62568,685
        10         20         30         40         50         60 
MPGTKRFQHV IETPEPGKWE LSGYEAAVPI TEKSNPLTQD LDKADAENIV RLLGQCDAEI 

        70         80         90        100        110        120 
FQEEGQALST YQRLYSESIL TTMVQVAGKV QEVLKEPDGG LVVLSGGGTS GRMAFLMSVS 

       130        140        150        160        170        180 
FNQLMKGLGQ KPLYTYLIAG GDRSVVASRE GTEDSALHGI EELKKVAAGK KRVIVIGISV 

       190        200        210        220        230        240 
GLSAPFVAGQ MDCCMNNTAV FLPVLVGFNP VSMARNDPIE DWSSTFRQVA ERMQKMQEKQ 

       250        260        270        280        290        300 
KAFVLNPAIG PEGLSGSSRM KGGSATKILL ETLLLAAHKT VDQGIAASQR CLLEILRTFE 

       310        320        330        340        350        360 
RAHQVTYSQS PKIATLMKSV STSLEKKGHV YLVGWQTLGI IAIMDGVECI HTFGADFRDV 

       370        380        390        400        410        420 
RGFLIGDHSD MFNQKAELTN QGPQFTFSQE DFLTSILPSL TEIDTVVFIF TLDDNLTEVQ 

       430        440        450        460        470        480 
TIVEQVKEKT NHIQALAHST VGQTLPIPLK KLFPSIISIT WPLLFFEYEG NFIQKFQREL 

       490        500        510        520        530        540 
STKWVLNTVS TGAHVLLGKI LQNHMLDLRI SNSKLFWRAL AMLQRFSGQS KARCIESLLR 

       550        560        570        580        590        600 
AIHFPQPLSD DIRAAPISCH VQVAHEKEQV IPIALLSLLF RCSITEAQAH LAAAPSVCEA 

       610        620 
VRSALAGPGQ KRTADPLEIL EPDVQ 

« Hide

Isoform 2 [UniParc].

Checksum: B958AFB4A930F3B1
Show »

FASTA15016,477

References

« Hide 'large scale' references
[1]"Human glucokinase regulatory protein (GCKR): cDNA and genomic cloning, complete primary structure, and chromosomal localization."
Warner J.P., Leek J.P., Intody S., Markham A.F., Bonthron D.T.
Mamm. Genome 6:532-536(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
Tissue: Hepatoblastoma.
[2]"Organization of the human glucokinase regulator gene GCKR."
Hayward B.E., Dunlop N., Intody S., Leek J.P., Markham A.F., Warner J.P., Bonthron D.T.
Genomics 49:137-142(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: PARTIAL NUCLEOTIDE SEQUENCE [GENOMIC DNA], SEQUENCE REVISION TO 393 AND 560, TISSUE SPECIFICITY.
[3]NIEHS SNPs program
Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS GLY-77; SER-256; LEU-446 AND GLN-540.
[4]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
Tissue: Liver.
[5]"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. expand/collapse author list , 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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], VARIANT LEU-446.
[6]"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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[7]"Glucokinase regulatory protein is essential for the proper subcellular localisation of liver glucokinase."
de la Iglesia N., Veiga-da-Cunha M., Van Schaftingen E., Guinovart J.J., Ferrer J.C.
FEBS Lett. 456:332-338(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, SUBUNIT.
[8]"The common P446L polymorphism in GCKR inversely modulates fasting glucose and triglyceride levels and reduces type 2 diabetes risk in the DESIR prospective general French population."
Vaxillaire M., Cavalcanti-Proenca C., Dechaume A., Tichet J., Marre M., Balkau B., Froguel P.
Diabetes 57:2253-2257(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INVOLVEMENT IN FGQTL5, VARIANT LEU-446, ASSOCIATION WITH LOWER RISK FOR DIABETES TYPE 2.
[9]"The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver."
Beer N.L., Tribble N.D., McCulloch L.J., Roos C., Johnson P.R., Orho-Melander M., Gloyn A.L.
Hum. Mol. Genet. 18:4081-4088(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY, CHARACTERIZATION OF VARIANT LEU-446.
[10]"Molecular basis for the role of glucokinase regulatory protein as the allosteric switch for glucokinase."
Choi J.M., Seo M.H., Kyeong H.H., Kim E., Kim H.S.
Proc. Natl. Acad. Sci. U.S.A. 110:10171-10176(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH GCK, MUTAGENESIS OF ASP-413 AND 463-LEU--PHE-465.
[11]"Crystal structure of glucokinase regulatory protein."
Pautsch A., Stadler N., Lohle A., Rist W., Berg A., Glocker L., Nar H., Reinert D., Lenter M., Heckel A., Schnapp G., Kauschke S.G.
Biochemistry 52:3523-3531(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.47 ANGSTROMS) IN COMPLEX WITH FRUCTOSE-1-PHOSPHATE, FUNCTION, INTERACTION WITH GCK, MUTAGENESIS OF 326-LYS-LYS-327 AND 450-LYS-LYS-451.
[12]"Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations."
Orho-Melander M., Melander O., Guiducci C., Perez-Martinez P., Corella D., Roos C., Tewhey R., Rieder M.J., Hall J., Abecasis G., Tai E.S., Welch C., Arnett D.K., Lyssenko V., Lindholm E., Saxena R., de Bakker P.I., Burtt N. expand/collapse author list , Voight B.F., Hirschhorn J.N., Tucker K.L., Hedner T., Tuomi T., Isomaa B., Eriksson K.F., Taskinen M.R., Wahlstrand B., Hughes T.E., Parnell L.D., Lai C.Q., Berglund G., Peltonen L., Vartiainen E., Jousilahti P., Havulinna A.S., Salomaa V., Nilsson P., Groop L., Altshuler D., Ordovas J.M., Kathiresan S.
Diabetes 57:3112-3121(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT LEU-446, INVOLVEMENT IN FGQTL5, ASSOCIATION WITH HIGH PLASMA TRIGLYCERIDE LEVELS.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
Z48475 mRNA. Translation: CAA88367.1.
Y09593 Genomic DNA. Translation: CAA70779.2.
Y09592 Genomic DNA. Translation: CAB61828.1.
AY320034 Genomic DNA. Translation: AAP72013.1.
AK298448 mRNA. Translation: BAG60664.1.
AC074117 Genomic DNA. Translation: AAY14850.1.
BC130481 mRNA. Translation: AAI30482.1.
BC130483 mRNA. Translation: AAI30484.1.
CCDSCCDS1757.1.
PIRS52485.
RefSeqNP_001477.2. NM_001486.3.
UniGeneHs.89771.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
4BB9X-ray1.47A1-625[»]
4BBAX-ray1.92A1-625[»]
4LY9X-ray2.35A/B1-625[»]
4MQUX-ray2.22A/B1-625[»]
4MROX-ray2.20A/B1-625[»]
4MSUX-ray2.50A/B1-625[»]
ProteinModelPortalQ14397.
SMRQ14397. Positions 6-605.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid108916. 4 interactions.
IntActQ14397. 2 interactions.
STRING9606.ENSP00000264717.

Chemistry

ChEMBLCHEMBL1075152.

PTM databases

PhosphoSiteQ14397.

Polymorphism databases

DMDM327478611.

Proteomic databases

PaxDbQ14397.
PRIDEQ14397.

Protocols and materials databases

DNASU2646.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000264717; ENSP00000264717; ENSG00000084734.
ENST00000417872; ENSP00000398303; ENSG00000084734.
GeneID2646.
KEGGhsa:2646.
UCSCuc002rky.3. human. [Q14397-1]

Organism-specific databases

CTD2646.
GeneCardsGC02P027720.
H-InvDBHIX0030026.
HGNCHGNC:4196. GCKR.
HPACAB034098.
HPA045855.
HPA057478.
MIM600842. gene.
613463. phenotype.
neXtProtNX_Q14397.
PharmGKBPA28611.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG2103.
HOGENOMHOG000031501.
HOVERGENHBG005818.
InParanoidQ14397.
OrthoDBEOG7HXCRC.
PhylomeDBQ14397.
TreeFamTF329177.

Enzyme and pathway databases

ReactomeREACT_111217. Metabolism.
REACT_116125. Disease.
REACT_15518. Transmembrane transport of small molecules.

Gene expression databases

ArrayExpressQ14397.
BgeeQ14397.
CleanExHS_GCKR.
GenevestigatorQ14397.

Family and domain databases

InterProIPR005486. Glucokinase_regulatory_CS.
IPR001347. SIS.
[Graphical view]
PROSITEPS01272. GCKR. 1 hit.
PS51464. SIS. 2 hits.
[Graphical view]
ProtoNetSearch...

Other

GenomeRNAi2646.
NextBio10442.
PROQ14397.
SOURCESearch...

Entry information

Entry nameGCKR_HUMAN
AccessionPrimary (citable) accession number: Q14397
Secondary accession number(s): A1L4C2 expand/collapse secondary AC list , B4DPQ2, Q53RY6, Q99522
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: April 5, 2011
Last modified: July 9, 2014
This is version 114 of the entry and version 6 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 2

Human chromosome 2: entries, gene names and cross-references to MIM