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Protein

G protein pathway suppressor 2

Gene

GPS2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Key regulator of inflammation, lipid metabolism and mitochondrion homeostasis that acts by inhibiting the activity of the ubiquitin-conjugating enzyme UBE2N/Ubc13, thereby inhibiting 'Lys-63'-linked ubiquitination (By similarity). In the nucleus, can both acts as a corepressor and coactivator of transcription, depending on the context (PubMed:24943844). Acts as a transcription coactivator in adipocytes by promoting the recruitment of PPARG to promoters: acts by inhibiting the activity of the ubiquitin-conjugating enzyme UBE2N/Ubc13, leading to stabilization of KDM4A and subsequent histone H3 'Lys-9' (H3K9) demethylation (By similarity). Promotes cholesterol efflux by acting as a transcription coactivator (PubMed:19481530). Acts as a regulator of B-cell development by inhibiting UBE2N/Ubc13, thereby restricting the activation of Toll-like receptors (TLRs) and B-cell antigen receptors (BCRs) signaling pathways (By similarity). Acts as a key mediator of mitochondrial stress response: in response to mitochondrial depolarization, relocates from the mitochondria to the nucleus following desumoylation and specifically promotes expression of nuclear-encoded mitochondrial genes (PubMed:29499132). Promotes transcription of nuclear-encoded mitochondrial genes by inhibiting UBE2N/Ubc13 (PubMed:29499132). Can also act as a corepressor as part of the N-Cor repressor complex by repressing active PPARG (PubMed:19858209, PubMed:24943844). Plays an anti-inflammatory role in macrophages and is required for insulin sensitivity by acting as a corepressor (By similarity). Plays an anti-inflammatory role during the hepatic acute phase response by interacting with sumoylated NR1H2 and NR5A2 proteins, thereby preventing N-Cor corepressor complex dissociation (PubMed:20159957). In the cytosol, also plays a non-transcriptional role by regulating insulin signaling and pro-inflammatory pathways (By similarity). In the cytoplasm, acts as a negative regulator of inflammation by inhibiting the proinflammatory TNF-alpha pathway; acts by repressing UBE2N/Ubc13 activity (By similarity). In the cytoplasm of adipocytes, restricts the activation of insulin signaling via inhibition of UBE2N/Ubc13-mediated ubiquitination of AKT (By similarity). Able to suppress G-protein- and mitogen-activated protein kinase-mediated signal transduction (PubMed:8943324). Acts as a tumor-suppressor in liposarcoma (PubMed:27460081).By similarity7 Publications
(Microbial infection) Required for efficient replication of hepatitis C virus (HCV) by promoting the interaction between VAPA and HCV virus protein NS5A.1 Publication

GO - Molecular functioni

  • cyclin binding Source: UniProtKB
  • GTPase inhibitor activity Source: ProtInc
  • transcription coactivator activity Source: UniProtKB
  • transcription corepressor activity Source: UniProtKB

GO - Biological processi

Keywordsi

Molecular functionActivator, Repressor
Biological processHost-virus interaction, Transcription, Transcription regulation

Enzyme and pathway databases

ReactomeiR-HSA-1989781 PPARA activates gene expression
R-HSA-3214815 HDACs deacetylate histones

Names & Taxonomyi

Protein namesi
Recommended name:
G protein pathway suppressor 22 Publications
Short name:
GPS-21 Publication
Gene namesi
Name:GPS2Imported
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 17

Organism-specific databases

EuPathDBiHostDB:ENSG00000132522.15
HGNCiHGNC:4550 GPS2
MIMi601935 gene
neXtProtiNX_Q13227

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Mitochondrion, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi19 – 22HRHI → AEHA: Abolishes interaction with TBL1X. 1 Publication4
Mutagenesisi45K → R: Abolishes sumoylation; when associated with R-71. 1 Publication1
Mutagenesisi61 – 94Missing : Abolishes interaction with sumoylated NR1H2 and NR5A2 proteins. 1 PublicationAdd BLAST34
Mutagenesisi69 – 70IL → AA: Weakly affects interaction with sumoylated NR1H2 and NR5A2 proteins. 1 Publication2
Mutagenesisi71K → R: Abolishes sumoylation; when associated with R-45. 1 Publication1
Mutagenesisi76 – 79LLAL → RRAR: Weakly affects interaction with sumoylated NR1H2 and NR5A2 proteins. 1 Publication4
Mutagenesisi86 – 90LFLQL → RFRQR: Weakly affects interaction with sumoylated NR1H2 and NR5A2 proteins. 1 Publication5
Mutagenesisi319S → A: Does not affect methylation. 1 Publication1
Mutagenesisi320Q → A: Does not affect methylation. 1 Publication1
Mutagenesisi321N → A: Strongly decreases methylation. 1 Publication1
Mutagenesisi322P → A: Strongly decreases methylation. 1 Publication1
Mutagenesisi324F → A: Abolishes methylation. 1 Publication1
Mutagenesisi325Y → A: Abolishes methylation. 1 Publication1
Mutagenesisi327K → A: Decreases methylation. 1 Publication1

Keywords - Diseasei

Tumor suppressor

Organism-specific databases

DisGeNETi2874
OpenTargetsiENSG00000132522
PharmGKBiPA28945

Polymorphism and mutation databases

BioMutaiGPS2
DMDMi6226623

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000875651 – 327G protein pathway suppressor 2Add BLAST327

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Cross-linki45Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1)1 Publication
Cross-linki71Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1)1 Publication
Modified residuei312Asymmetric dimethylarginineCombined sources1
Modified residuei323Asymmetric dimethylarginine; alternateCombined sources1 Publication1
Modified residuei323Omega-N-methylarginine; alternate1 Publication1

Post-translational modificationi

Sumoylation regulates its subcellular location (PubMed:24943844). Sumoylation at Lys-45 and Lys-71 regulates the shuttling between the cytoplasm and the nucleus (PubMed:24943844). Sumoylation at Lys-71 is required for interaction with TBL1X (By similarity). Sumoylated at Lys-45 and Lys-71 in mitochondrion (By similarity). Desumoylation by SENP1 leads to relocation from the mitochondria to the nucleus (By similarity).By similarity1 Publication
Ubiquitinated at the C-terminus by SIAH2; leading to its degradation by the proteasome. Interaction with TBL1X and methylation at Arg-323 protect GPS2 against ubiquitination and degradation.By similarity
Methylated at Arg-312 and Arg-323 by PRMT6. Methylation at Arg-323 protects from degradation by the proteasome.By similarity

Keywords - PTMi

Isopeptide bond, Methylation, Ubl conjugation

Proteomic databases

EPDiQ13227
PaxDbiQ13227
PeptideAtlasiQ13227
PRIDEiQ13227
ProteomicsDBi59233

PTM databases

iPTMnetiQ13227
PhosphoSitePlusiQ13227

Expressioni

Tissue specificityi

Widely expressed.1 Publication

Inductioni

Down-regulated in liposarcoma (PubMed:27460081). Down-regulated in macrophages of patients with adipose tissue inflammation and type-2 diabetes (PubMed:27270589).2 Publications

Gene expression databases

BgeeiENSG00000132522 Expressed in 92 organ(s), highest expression level in testis
CleanExiHS_GPS2
ExpressionAtlasiQ13227 baseline and differential
GenevisibleiQ13227 HS

Organism-specific databases

HPAiHPA067540

Interactioni

Subunit structurei

Component of the N-Cor repressor complex, at least composed of NCOR1, NCOR2, HDAC3, TBL1X, TBL1R, CORO2A and GPS2 (PubMed:11931768, PubMed:19858209, PubMed:21240272). Interacts (when sumoylated at Lys-71) with TBL1X; leading to protect GPS2 from degradation by the proteasome (PubMed:24943844, PubMed:21240272). Interacts with UBE2N; leading to inhibit UBE2N/Ubc13 activity (By similarity). Interacts with TRAF1 (By similarity). Interacts with TRAF2 (By similarity). Interacts with TRAF6 (By similarity). Interacts with PPARG (when in the liganded conformation) (By similarity). Interacts with (sumoylated) NR1H2; interaction with sumoylated NR1H2 and NR5A2 onto hepatic acute phase protein promoters prevents N-Cor corepressor complex dissociation (PubMed:20159957). Interacts with (sumoylated) NR5A2; interaction with sumoylated NR1H2 and NR5A2 onto hepatic acute phase protein promoters prevents N-Cor corepressor complex dissociation (PubMed:20159957). Interacts with NR1H3 (PubMed:19481530). Interacts with RFX4 (By similarity). Interacts with ANKRD26 (PubMed:22666460).By similarity1 Publication6 Publications
(Microbial infection) Interacts (via coiled coil domain) with hepatitis C virus (HCV) NS5A.1 Publication

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi109132, 67 interactors
CORUMiQ13227
DIPiDIP-34427N
IntActiQ13227, 77 interactors
MINTiQ13227
STRINGi9606.ENSP00000370104

Structurei

Secondary structure

1327
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliQ13227
SMRiQ13227
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni61 – 94interaction with SUMO1 PublicationAdd BLAST34

Coiled coil

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Coiled coili14 – 109Sequence analysisAdd BLAST96

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi32 – 35Poly-Glu4

Keywords - Domaini

Coiled coil

Phylogenomic databases

eggNOGiENOG410IH6X Eukaryota
ENOG4110MFH LUCA
GeneTreeiENSGT00390000004049
HOGENOMiHOG000112796
HOVERGENiHBG005905
InParanoidiQ13227
KOiK15307
OMAiPYAVHSH
OrthoDBiEOG091G0ET5
PhylomeDBiQ13227
TreeFamiTF329067

Family and domain databases

InterProiView protein in InterPro
IPR026094 GPS2
PANTHERiPTHR22654 PTHR22654, 1 hit
PfamiView protein in Pfam
PF15991 G_path_suppress, 1 hit

Sequences (2+)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

This entry has 2 described isoforms and 4 potential isoforms that are computationally mapped.iShow all

Isoform 1 (identifier: Q13227-1) [UniParc]FASTAAdd to basket

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.

« Hide
        10         20         30         40         50
MPALLERPKL SNAMARALHR HIMMERERKR QEEEEVDKMM EQKMKEEQER
60 70 80 90 100
RKKKEMEERM SLEETKEQIL KLEEKLLALQ EEKHQLFLQL KKVLHEEEKR
110 120 130 140 150
RRKEQSDLTT LTSAAYQQSL TVHTGTHLLS MQGSPGGHNR PGTLMAADRA
160 170 180 190 200
KQMFGPQVLT TRHYVGSAAA FAGTPEHGQF QGSPGGAYGT AQPPPHYGPT
210 220 230 240 250
QPAYSPSQQL RAPSAFPAVQ YLSQPQPQPY AVHGHFQPTQ TGFLQPGGAL
260 270 280 290 300
SLQKQMEHAN QQTGFSDSSS LRPMHPQALH PAPGLLASPQ LPVQMQPAGK
310 320
SGFAATSQPG PRLPFIQHSQ NPRFYHK
Length:327
Mass (Da):36,689
Last modified:May 30, 2000 - v3
Checksum:iAE65DA578C978C9B
GO
Isoform 2 (identifier: Q13227-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     301-327: SGFAATSQPGPRLPFIQHSQNPRFYHK → TAP

Note: No experimental confirmation available.
Show »
Length:303
Mass (Da):33,907
Checksum:i92B89119643D2D42
GO

Computationally mapped potential isoform sequencesi

There are 4 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
I3L3Y9I3L3Y9_HUMAN
G protein pathway suppressor 2
GPS2
327Annotation score:
I3L4X7I3L4X7_HUMAN
G protein pathway suppressor 2
GPS2
259Annotation score:
I3L1H4I3L1H4_HUMAN
G protein pathway suppressor 2
GPS2
158Annotation score:
I3L242I3L242_HUMAN
G protein pathway suppressor 2
GPS2
73Annotation score:

Sequence cautioni

The sequence CAB75677 differs from that shown. Reason: Erroneous translation. Wrong choice of frame.Curated

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_021972306T → A. Corresponds to variant dbSNP:rs2292065Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_057012301 – 327SGFAA…RFYHK → TAP in isoform 2. 1 PublicationAdd BLAST27

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U28963 mRNA Translation: AAB60432.1
BT006998 mRNA Translation: AAP35644.1
AK301877 mRNA Translation: BAG63313.1
CR541723 mRNA Translation: CAG46524.1
CR541750 mRNA Translation: CAG46550.1
AL122080 mRNA Translation: CAB59255.1
AL157493 mRNA Translation: CAB75677.2 Sequence problems.
AC026954 Genomic DNA No translation available.
BC013652 mRNA Translation: AAH13652.1
BC103901 mRNA Translation: AAI03902.1
BC103903 mRNA Translation: AAI03904.1
BC107738 mRNA Translation: AAI07739.1
CCDSiCCDS11100.1 [Q13227-1]
PIRiT34562
RefSeqiNP_004480.1, NM_004489.4 [Q13227-1]
UniGeneiHs.438219

Genome annotation databases

EnsembliENST00000380728; ENSP00000370104; ENSG00000132522 [Q13227-1]
ENST00000389167; ENSP00000379841; ENSG00000132522 [Q13227-1]
GeneIDi2874
KEGGihsa:2874
UCSCiuc002gfx.2 human [Q13227-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiGPS2_HUMAN
AccessioniPrimary (citable) accession number: Q13227
Secondary accession number(s): B4DXA1, Q6FHM8
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: May 30, 2000
Last modified: September 12, 2018
This is version 148 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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