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Protein

G protein pathway suppressor 2

Gene

Gps2

Organism
Mus musculus (Mouse)
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 (PubMed:22424771, PubMed:24953653, PubMed:28039360, PubMed:28123943, PubMed:29499132). In the nucleus, can both acts as a corepressor and coactivator of transcription, depending on the context (PubMed:18218630, PubMed:24953653, PubMed:25519902, PubMed:27270589, PubMed:28039360). 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 (PubMed:22666460, PubMed:24953653). Promotes cholesterol efflux by acting as a transcription coactivator (By similarity). 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 (PubMed:28039360). 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:25519902). Plays an anti-inflammatory role in macrophages and is required for insulin sensitivity by acting as a corepressor (PubMed:27270589). 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 (By similarity). In the cytosol, also plays a non-transcriptional role by regulating insulin signaling and pro-inflammatory pathways (PubMed:22424771, PubMed:28123943). In the cytoplasm, acts as a negative regulator of inflammation by inhibiting the proinflammatory TNF-alpha pathway; acts by repressing UBE2N/Ubc13 activity (PubMed:22424771). In the cytoplasm of adipocytes, restricts the activation of insulin signaling via inhibition of UBE2N/Ubc13-mediated ubiquitination of AKT (PubMed:28123943). Able to suppress G-protein- and mitogen-activated protein kinase-mediated signal transduction (By similarity).By similarity9 Publications

GO - Molecular functioni

  • cyclin binding Source: MGI
  • transcription coactivator activity Source: UniProtKB
  • transcription corepressor activity Source: UniProtKB

GO - Biological processi

  • B cell differentiation Source: UniProtKB
  • negative regulation of B cell receptor signaling pathway Source: UniProtKB
  • negative regulation of fat cell differentiation Source: UniProtKB
  • negative regulation of inflammatory response Source: UniProtKB
  • negative regulation of JNK cascade Source: UniProtKB
  • negative regulation of protein K63-linked ubiquitination Source: UniProtKB
  • negative regulation of toll-like receptor signaling pathway Source: UniProtKB
  • negative regulation of transcription by RNA polymerase II Source: UniProtKB
  • negative regulation of tumor necrosis factor-mediated signaling pathway Source: UniProtKB
  • positive regulation of cholesterol efflux Source: UniProtKB
  • positive regulation of peroxisome proliferator activated receptor signaling pathway Source: UniProtKB
  • positive regulation of transcription by RNA polymerase II Source: UniProtKB
  • regulation of fat cell differentiation Source: UniProtKB
  • regulation of lipid metabolic process Source: UniProtKB
  • response to mitochondrial depolarisation Source: UniProtKB

Keywordsi

Molecular functionActivator, Repressor
Biological processTranscription, Transcription regulation

Names & Taxonomyi

Protein namesi
Recommended name:
G protein pathway suppressor 21 Publication
Short name:
GPS-21 Publication
Gene namesi
Name:Gps21 PublicationImported
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 11

Organism-specific databases

MGIiMGI:1891751 Gps2

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

Disruption phenotypei

Embryonic lethality (PubMed:25519902). Embryonic fibroblast cells show reduced corepressor function of the N-CoR complex for PPARG, leading to constitutive activation of PPARG target genes and spontaneous adipogenesis of the cells (PubMed:25519902). Conditional knockout mice lacking Gps2 in B-cells show developmental defects at multiple stages of B-cell differentiation, caused by of aberrant activation of 'Lys-63'-linked ubiquitination events and altered gene expression programs downstream of the misregulated signaling pathways (PubMed:28039360). Conditional knockout mice lacking Gps2 in macrophages show inappropriate corepressor complex function, leading to enhancer activation, pro-inflammatory gene expression and hypersensitivity toward metabolic-stress signals (PubMed:27270589). Conditional knockout mice lacking Gps2 in adipose tissues show obesity associated with constitutive insulin signaling, increased lipid deposition in the white adipose tissue and improved systemic insulin sensitivity (PubMed:28123943). Conditional knockout mice lacking Gps2 in adipose tissues display reduced mitochondrial content in brown adipose tissue (PubMed:29499132).5 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi45K → R: Decreased stability of the protein, probably due inability to interact with TBL1X; when associated with R-71. Abolishes sumoylation; when associated with R-71. 1 Publication1
Mutagenesisi52 – 53KK → AA: Does not affect localization to the nucleus. 1 Publication2
Mutagenesisi71K → R: Decreased stability of the protein, probably due inability to interact with TBL1X; when associated with R-45. Abolishes sumoylation; when associated with R-45. 2 Publications1
Mutagenesisi254K → A: Increased stability due to impaired ubiquitination; when associated with A-300 and A-327. 1 Publication1
Mutagenesisi300K → A: Increased stability due to impaired ubiquitination; when associated with A-254 and A-327. 1 Publication1
Mutagenesisi312R → A: Abolished methylation; when associated with A-323. 1 Publication1
Mutagenesisi323R → A: Promotes ubiquitination and degradation by the proteasome. Abolished methylation; when associated with A-312. 1 Publication1
Mutagenesisi327K → A: Increased stability due to impaired ubiquitination; when associated with A-254 and A-300. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00004418031 – 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)2 Publications
Cross-linki71Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1)2 Publications
Modified residuei312Asymmetric dimethylarginineCombined sources1 Publication1
Modified residuei323Asymmetric dimethylarginine; alternateCombined sources1 Publication1
Modified residuei323Omega-N-methylarginine; alternateBy similarity1

Post-translational modificationi

Sumoylation regulates its subcellular location (PubMed:26070566, PubMed:29499132). Sumoylation at Lys-45 and Lys-71 regulates the shuttling between the cytoplasm and the nucleus (By similarity). Sumoylation at Lys-71 is required for interaction with TBL1X (PubMed:26070566). Sumoylated at Lys-45 and Lys-71 in mitochondrion (PubMed:29499132). Desumoylation by SENP1 leads to relocation from the mitochondria to the nucleus (PubMed:29499132).By similarity2 Publications
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.1 Publication
Methylated at Arg-312 and Arg-323 by PRMT6. Methylation at Arg-323 protects from degradation by the proteasome.1 Publication

Keywords - PTMi

Isopeptide bond, Methylation, Ubl conjugation

Proteomic databases

MaxQBiQ921N8
PaxDbiQ921N8
PeptideAtlasiQ921N8
PRIDEiQ921N8

PTM databases

iPTMnetiQ921N8
PhosphoSitePlusiQ921N8

Expressioni

Gene expression databases

BgeeiENSMUSG00000023170
ExpressionAtlasiQ921N8 baseline and differential

Interactioni

Subunit structurei

Component of the N-Cor repressor complex, at least composed of NCOR1, NCOR2, HDAC3, TBL1X, TBL1R, CORO2A and GPS2 (PubMed:25519902). Interacts (when sumoylated at Lys-71) with TBL1X; leading to protect GPS2 from degradation by the proteasome (PubMed:26070566). Interacts with UBE2N; leading to inhibit UBE2N/Ubc13 activity (PubMed:22424771). Interacts with TRAF1 (PubMed:22424771). Interacts with TRAF2 (PubMed:22424771). Interacts with TRAF6 (PubMed:22424771). Interacts with PPARG (when in the liganded conformation) (PubMed:25519902). Interacts with (sumoylated) NR1H2; interaction with sumoylated NR1H2 and NR5A2 onto hepatic acute phase protein promoters prevents N-Cor corepressor complex dissociation (By similarity). Interacts with (sumoylated) NR5A2; interaction with sumoylated NR1H2 and NR5A2 onto hepatic acute phase protein promoters prevents N-Cor corepressor complex dissociation (By similarity). Interacts with NR1H3 (By similarity). Interacts with RFX4 (PubMed:18218630). Interacts with ANKRD26 (By similarity).By similarity4 Publications

GO - Molecular functioni

Protein-protein interaction databases

STRINGi10090.ENSMUSP00000054072

Structurei

3D structure databases

SMRiQ921N8
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni61 – 94interaction with SUMOBy similarityAdd BLAST34

Coiled coil

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

Keywords - Domaini

Coiled coil

Phylogenomic databases

eggNOGiENOG410IH6X Eukaryota
ENOG4110MFH LUCA
GeneTreeiENSGT00390000004049
HOGENOMiHOG000112796
HOVERGENiHBG005905
KOiK15307
OMAiPYAVHSH
OrthoDBiEOG091G0ET5
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

Sequencei

Sequence statusi: Complete.

Q921N8-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MPALLERPKL SNAMARALHR HIMMERERKR QEEEEVDKMM EQKMKEEQER
60 70 80 90 100
RKKKEMEERM SLEETKEQIL KLQEKLSALQ 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 TGFLQPGSTL
260 270 280 290 300
SLQKQMEHAN QQTSFSDSSS LRPMHPQALH PAPGLLASPQ LPVQIQAAGK
310 320
SGFATTSQPG PRLPFIQHSQ NPRFYHK
Length:327
Mass (Da):36,738
Last modified:December 1, 2001 - v1
Checksum:i3008661CE6579F4B
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AL596185 Genomic DNA No translation available.
CH466596 Genomic DNA Translation: EDL12472.1
CH466596 Genomic DNA Translation: EDL12474.1
BC011317 mRNA Translation: AAH11317.1
BC138879 mRNA Translation: AAI38880.1
BC138880 mRNA Translation: AAI38881.1
CCDSiCCDS24922.1
RefSeqiNP_062700.2, NM_019726.3
XP_006533850.1, XM_006533787.2
UniGeneiMm.477738

Genome annotation databases

EnsembliENSMUST00000057884; ENSMUSP00000054072; ENSMUSG00000023170
ENSMUST00000072581; ENSMUSP00000072389; ENSMUSG00000023170
ENSMUST00000116358; ENSMUSP00000112062; ENSMUSG00000023170
GeneIDi56310
KEGGimmu:56310
UCSCiuc007jsp.1 mouse

Similar proteinsi

Entry informationi

Entry nameiGPS2_MOUSE
AccessioniPrimary (citable) accession number: Q921N8
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 25, 2017
Last sequence update: December 1, 2001
Last modified: May 23, 2018
This is version 106 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

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