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Protein

Leucine-rich repeat-containing G-protein coupled receptor 4

Gene

Lgr4

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Receptor for R-spondins that potentiates the canonical Wnt signaling pathway and is involved in the formation of various organs. Upon binding to R-spondins (RSPO1, RSPO2, RSPO3 or RSPO4), associates with phosphorylated LRP6 and frizzled receptors that are activated by extracellular Wnt receptors, triggering the canonical Wnt signaling pathway to increase expression of target genes. In contrast to classical G-protein coupled receptors, does not activate heterotrimeric G-proteins to transduce the signal. Its function as activator of the Wnt signaling pathway is required for the development of various organs, including liver, kidney, intestine, bone, reproductive tract and eye. May also act as a receptor for norrin (NDP), such results however require additional confirmation in vivo. Required during spermatogenesis to activate the Wnt signaling pathway in peritubular myoid cells. Required for the maintenance of intestinal stem cells and Paneth cell differentiation in postnatal intestinal crypts. Acts as a regulator of bone formation and remodeling. Involved in kidney development; required for maintaining the ureteric bud in an undifferentiated state. Involved in the development of the anterior segment of the eye. Required during erythropoiesis. Also acts as a negative regulator of innate immunity by inhibiting TLR2/TLR4 associated pattern-recognition and proinflammatory cytokine production. Plays an important role in regulating the circadian rhythms of plasma lipids, partially through regulating the rhythmic expression of MTTP (PubMed:24353284).10 Publications

GO - Molecular functioni

  • transmembrane signaling receptor activity Source: UniProtKB

GO - Biological processi

  • bone mineralization Source: UniProtKB
  • bone remodeling Source: UniProtKB
  • canonical Wnt signaling pathway involved in metanephric kidney development Source: UniProtKB
  • cell differentiation involved in metanephros development Source: UniProtKB
  • circadian regulation of gene expression Source: UniProtKB
  • circadian rhythm Source: UniProtKB
  • digestive tract development Source: MGI
  • epithelial cell proliferation Source: MGI
  • epithelial cell proliferation involved in renal tubule morphogenesis Source: MGI
  • G-protein coupled receptor signaling pathway Source: UniProtKB-KW
  • hair follicle development Source: MGI
  • innate immune response Source: UniProtKB-KW
  • intestinal stem cell homeostasis Source: MGI
  • male genitalia development Source: MGI
  • metanephric glomerulus development Source: UniProtKB
  • metanephric nephron tubule morphogenesis Source: UniProtKB
  • negative regulation of cytokine secretion Source: UniProtKB
  • negative regulation of toll-like receptor signaling pathway Source: UniProtKB
  • negative regulation of transcription, DNA-templated Source: UniProtKB
  • osteoblast differentiation Source: UniProtKB
  • positive regulation of branching involved in ureteric bud morphogenesis Source: UniProtKB
  • positive regulation of canonical Wnt signaling pathway Source: UniProtKB
  • positive regulation of transcription, DNA-templated Source: UniProtKB
  • spermatogenesis Source: UniProtKB
  • tube morphogenesis Source: MGI
Complete GO annotation...

Keywords - Molecular functioni

Developmental protein, G-protein coupled receptor, Receptor, Transducer

Keywords - Biological processi

Biological rhythms, Differentiation, Immunity, Innate immunity, Spermatogenesis, Wnt signaling pathway

Enzyme and pathway databases

ReactomeiR-MMU-4641263. Regulation of FZD by ubiquitination.

Names & Taxonomyi

Protein namesi
Recommended name:
Leucine-rich repeat-containing G-protein coupled receptor 4
Alternative name(s):
G-protein coupled receptor 48
Gene namesi
Name:Lgr4
Synonyms:Gpr48
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 2

Organism-specific databases

MGIiMGI:1891468. Lgr4.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini25 – 544ExtracellularSequence analysisAdd BLAST520
Transmembranei545 – 565Helical; Name=1Sequence analysisAdd BLAST21
Topological domaini566 – 575CytoplasmicSequence analysis10
Transmembranei576 – 596Helical; Name=2Sequence analysisAdd BLAST21
Topological domaini597 – 619ExtracellularSequence analysisAdd BLAST23
Transmembranei620 – 640Helical; Name=3Sequence analysisAdd BLAST21
Topological domaini641 – 661CytoplasmicSequence analysisAdd BLAST21
Transmembranei662 – 682Helical; Name=4Sequence analysisAdd BLAST21
Topological domaini683 – 703ExtracellularSequence analysisAdd BLAST21
Transmembranei704 – 724Helical; Name=5Sequence analysisAdd BLAST21
Topological domaini725 – 756CytoplasmicSequence analysisAdd BLAST32
Transmembranei757 – 777Helical; Name=6Sequence analysisAdd BLAST21
Topological domaini778 – 783ExtracellularSequence analysis6
Transmembranei784 – 804Helical; Name=7Sequence analysisAdd BLAST21
Topological domaini805 – 951CytoplasmicSequence analysisAdd BLAST147

GO - Cellular componenti

  • integral component of plasma membrane Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Disruption phenotypei

Strong variations in phenotypes, probably depending on the strain background used in the different experiments. According to a first report done in a C57BL/6 background, mice show intra-uterine growth retardation leading to embryonic and perinatal lethality (PubMed:15192078). A lethal phenotype was confirmed by other groups. In some cases however, few mice survive until adulthood. Mice that survive show wide spectrum of anterior segment dysgenesis phenotypes, including microphthalmia, iris hypoplasia, irdiocorneal angle malformation, cornea dysgenesis and cataract (PubMed:18424556). Defects in osteoblast differentiation and mineralization during embryonic bone formation are also observed. Postnatal mice that survive show defects in bone remodeling (PubMed:19605502). According to other reports done in other strain backgrounds, mice do not die and display defects in the male reproductive tract during the postnatal period (PubMed:16406039, PubMed:17079737, PubMed:23533175). Mice also show small kidneys, in which the total number and density of the glomeruli are decreased (PubMed:16785743). The use of conditional knockouts, leads to defects in hair placode formation, possibly due to reduced keratinocyte migration (PubMed:17079737, PubMed:17850793). Decrease in epithelial cell proliferation and strong reduction in terminal differentiation of Paneth cells in postnatal intestinal crypts (PubMed:21508962, PubMed:23393138). Fetuses display transient anemia during midgestation and abnormal definitive erythropoiesis (PubMed:18955481). Mice are also more susceptible and have much higher mortality to lipopolysaccharide (LPS) stimulation due to over-activated innate immune response (PubMed:23589304). Conditional knockout of both Lgr4 and Lgr5 in the gut results in Wnt signaling inhibition and results in the rapid demise of intestinal crypts (PubMed:21727895).16 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi755T → I: Confers constitutive activity. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 24Sequence analysisAdd BLAST24
ChainiPRO_000030324025 – 951Leucine-rich repeat-containing G-protein coupled receptor 4Add BLAST927

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi29 ↔ 35PROSITE-ProRule annotation
Disulfide bondi33 ↔ 43PROSITE-ProRule annotation
Glycosylationi68N-linked (GlcNAc...)Sequence analysis1
Glycosylationi188N-linked (GlcNAc...)Sequence analysis1
Glycosylationi199N-linked (GlcNAc...)Sequence analysis1
Glycosylationi294N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi339 ↔ 364PROSITE-ProRule annotation
Disulfide bondi470 ↔ 522PROSITE-ProRule annotation
Disulfide bondi471 ↔ 476PROSITE-ProRule annotation
Glycosylationi505N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi618 ↔ 693PROSITE-ProRule annotation
Modified residuei920PhosphoserineBy similarity1

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein

Proteomic databases

MaxQBiA2ARI4.
PaxDbiA2ARI4.
PeptideAtlasiA2ARI4.
PRIDEiA2ARI4.

PTM databases

PhosphoSitePlusiA2ARI4.

Expressioni

Inductioni

Expressed in a circadian manner in the liver.1 Publication

Gene expression databases

BgeeiENSMUSG00000050199.
GenevisibleiA2ARI4. MM.

Interactioni

Protein-protein interaction databases

STRINGi10090.ENSMUSP00000047325.

Structurei

3D structure databases

ProteinModelPortaliA2ARI4.
SMRiA2ARI4.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini25 – 57LRRNTAdd BLAST33
Repeati58 – 79LRR 1Add BLAST22
Repeati82 – 103LRR 2Add BLAST22
Repeati106 – 127LRR 3Add BLAST22
Repeati130 – 151LRR 4Add BLAST22
Repeati154 – 177LRR 5Add BLAST24
Repeati178 – 199LRR 6Add BLAST22
Repeati202 – 223LRR 7Add BLAST22
Repeati226 – 247LRR 8Add BLAST22
Repeati249 – 270LRR 9Add BLAST22
Repeati273 – 294LRR 10Add BLAST22
Repeati320 – 341LRR 11Add BLAST22
Repeati344 – 365LRR 12Add BLAST22
Repeati366 – 387LRR 13Add BLAST22
Repeati390 – 411LRR 14Add BLAST22
Repeati414 – 435LRR 15Add BLAST22

Sequence similaritiesi

Belongs to the G-protein coupled receptor 1 family.PROSITE-ProRule annotation
Contains 15 LRR (leucine-rich) repeats.Curated
Contains 1 LRRNT domain.Curated

Keywords - Domaini

Leucine-rich repeat, Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG0619. Eukaryota.
KOG2087. Eukaryota.
COG4886. LUCA.
GeneTreeiENSGT00760000119088.
HOGENOMiHOG000231829.
HOVERGENiHBG031675.
InParanoidiA2ARI4.
KOiK04309.
OMAiCAAPCSC.
OrthoDBiEOG091G0QA0.
PhylomeDBiA2ARI4.
TreeFamiTF316814.

Family and domain databases

Gene3Di3.80.10.10. 3 hits.
InterProiIPR000276. GPCR_Rhodpsn.
IPR017452. GPCR_Rhodpsn_7TM.
IPR002131. Gphrmn_rcpt_fam.
IPR032675. L_dom-like.
IPR001611. Leu-rich_rpt.
IPR003591. Leu-rich_rpt_typical-subtyp.
IPR000372. LRRNT.
[Graphical view]
PfamiPF00001. 7tm_1. 1 hit.
PF13855. LRR_8. 4 hits.
PF01462. LRRNT. 1 hit.
[Graphical view]
PRINTSiPR00373. GLYCHORMONER.
PR00237. GPCRRHODOPSN.
SMARTiSM00369. LRR_TYP. 15 hits.
SM00013. LRRNT. 1 hit.
[Graphical view]
SUPFAMiSSF52058. SSF52058. 2 hits.
PROSITEiPS50262. G_PROTEIN_RECEP_F1_2. 1 hit.
PS51450. LRR. 15 hits.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

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

Isoform 1 (identifier: A2ARI4-1) [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
MPGPLRLLCF FALGLLGSAG PSGAAPPLCA APCSCDGDRR VDCSGKGLTA
60 70 80 90 100
VPEGLSAFTQ ALDISMNNIT QLPEDAFKNF PFLEELQLAG NDLSFIHPKA
110 120 130 140 150
LSGLKELKVL TLQNNQLKTV PSEAIRGLSA LQSLRLDANH ITSVPEDSFE
160 170 180 190 200
GLVQLRHLWL DDNILTEVPV RPLSNLPTLQ ALTLALNNIS SIPDFAFTNL
210 220 230 240 250
SSLVVLHLHN NKIKSLSQHC FDGLDNLETL DLNYNNLDEF PQAIKALPSL
260 270 280 290 300
KELGFHSNSI SVIPDGAFAG NPLLRTIHLY DNPLSFVGNS AFHNLSDLHS
310 320 330 340 350
LVIRGASLVQ WFPNLAGTVH LESLTLTGTK ISSIPDDLCQ NQKMLRTLDL
360 370 380 390 400
SYNDIRDLPS FNGCRALEEI SLQRNQISLI KETTFQGLTS LRILDLSRNL
410 420 430 440 450
IREIHSGAFA KLGTITNLDV SFNELTSFPT EGLNGLNQLK LVGNFQLKDA
460 470 480 490 500
LAARDFANLR SLSVPYAYQC CAFWGCDSYA NLNTEDNSPQ DHSVTKEKGA
510 520 530 540 550
TDAANATSTA ESEEHSQIII HCTPSTGAFK PCEYLLGSWM IRLTVWFIFL
560 570 580 590 600
VALLFNLLVI LTVFASCSSL PASKLFIGLI SVSNLLMGIY TGILTFLDAV
610 620 630 640 650
SWGRFAEFGI WWETGSGCKV AGSLAVFSSE SAVFLLTLAA VERSVFAKDV
660 670 680 690 700
MKNGKSSHLR QFQVAALVAL LGAAIAGCFP LFHGGQYSAS PLCLPFPTGE
710 720 730 740 750
TPSLGFTVTL VLLNSLAFLL MAIIYTKLYC NLEKEDPSEN SQSSMIKHVA
760 770 780 790 800
WLIFTNCIFF CPVAFFSFAP LITAISISPE IMKSVTLIFF PLPACLNPVL
810 820 830 840 850
YVFFNPKFKD DWKLLKRRVT RKHGSVSVSI SSQGGCGEQD FYYDCGMYSH
860 870 880 890 900
LQGNLTVCDC CESFLLTKPV SCKHLIKSHS CPVLTVASCQ RPEAYWSDCG
910 920 930 940 950
TQSAHSDYAD EEDSFVSDSS DQVQACGRAC FYQSRGFPLV RYAYNLPRVR

D
Length:951
Mass (Da):104,150
Last modified:February 20, 2007 - v1
Checksum:iAD41C68730A19C6B
GO
Isoform 2 (identifier: A2ARI4-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     62-85: Missing.

Show »
Length:927
Mass (Da):101,341
Checksum:i2290E2B445926227
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti668V → L in AAH56637 (PubMed:15489334).Curated1
Sequence conflicti684G → R in AAH56637 (PubMed:15489334).Curated1
Sequence conflicti730C → F in BAC31882 (PubMed:16141072).Curated1
Sequence conflicti928R → P in AAH56637 (PubMed:15489334).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_04713762 – 85Missing in isoform 2. CuratedAdd BLAST24

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AL845423, AL928922 Genomic DNA. Translation: CAM17466.1.
AL928922, AL845423 Genomic DNA. Translation: CAM24131.1.
BX294391 Genomic DNA. No translation available.
AY255619 mRNA. Translation: AAO85131.1.
AK044357 mRNA. Translation: BAC31882.1.
BC056637 mRNA. Translation: AAH56637.1.
CCDSiCCDS38195.1. [A2ARI4-1]
RefSeqiNP_766259.2. NM_172671.2. [A2ARI4-1]
UniGeneiMm.277351.
Mm.485992.

Genome annotation databases

EnsembliENSMUST00000046548; ENSMUSP00000047325; ENSMUSG00000050199. [A2ARI4-1]
ENSMUST00000111037; ENSMUSP00000106666; ENSMUSG00000050199. [A2ARI4-2]
GeneIDi107515.
KEGGimmu:107515.
UCSCiuc008lmq.1. mouse. [A2ARI4-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AL845423, AL928922 Genomic DNA. Translation: CAM17466.1.
AL928922, AL845423 Genomic DNA. Translation: CAM24131.1.
BX294391 Genomic DNA. No translation available.
AY255619 mRNA. Translation: AAO85131.1.
AK044357 mRNA. Translation: BAC31882.1.
BC056637 mRNA. Translation: AAH56637.1.
CCDSiCCDS38195.1. [A2ARI4-1]
RefSeqiNP_766259.2. NM_172671.2. [A2ARI4-1]
UniGeneiMm.277351.
Mm.485992.

3D structure databases

ProteinModelPortaliA2ARI4.
SMRiA2ARI4.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi10090.ENSMUSP00000047325.

Protein family/group databases

GPCRDBiSearch...

PTM databases

PhosphoSitePlusiA2ARI4.

Proteomic databases

MaxQBiA2ARI4.
PaxDbiA2ARI4.
PeptideAtlasiA2ARI4.
PRIDEiA2ARI4.

Protocols and materials databases

DNASUi107515.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000046548; ENSMUSP00000047325; ENSMUSG00000050199. [A2ARI4-1]
ENSMUST00000111037; ENSMUSP00000106666; ENSMUSG00000050199. [A2ARI4-2]
GeneIDi107515.
KEGGimmu:107515.
UCSCiuc008lmq.1. mouse. [A2ARI4-1]

Organism-specific databases

CTDi55366.
MGIiMGI:1891468. Lgr4.

Phylogenomic databases

eggNOGiKOG0619. Eukaryota.
KOG2087. Eukaryota.
COG4886. LUCA.
GeneTreeiENSGT00760000119088.
HOGENOMiHOG000231829.
HOVERGENiHBG031675.
InParanoidiA2ARI4.
KOiK04309.
OMAiCAAPCSC.
OrthoDBiEOG091G0QA0.
PhylomeDBiA2ARI4.
TreeFamiTF316814.

Enzyme and pathway databases

ReactomeiR-MMU-4641263. Regulation of FZD by ubiquitination.

Miscellaneous databases

ChiTaRSiLgr4. mouse.
PROiA2ARI4.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000050199.
GenevisibleiA2ARI4. MM.

Family and domain databases

Gene3Di3.80.10.10. 3 hits.
InterProiIPR000276. GPCR_Rhodpsn.
IPR017452. GPCR_Rhodpsn_7TM.
IPR002131. Gphrmn_rcpt_fam.
IPR032675. L_dom-like.
IPR001611. Leu-rich_rpt.
IPR003591. Leu-rich_rpt_typical-subtyp.
IPR000372. LRRNT.
[Graphical view]
PfamiPF00001. 7tm_1. 1 hit.
PF13855. LRR_8. 4 hits.
PF01462. LRRNT. 1 hit.
[Graphical view]
PRINTSiPR00373. GLYCHORMONER.
PR00237. GPCRRHODOPSN.
SMARTiSM00369. LRR_TYP. 15 hits.
SM00013. LRRNT. 1 hit.
[Graphical view]
SUPFAMiSSF52058. SSF52058. 2 hits.
PROSITEiPS50262. G_PROTEIN_RECEP_F1_2. 1 hit.
PS51450. LRR. 15 hits.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiLGR4_MOUSE
AccessioniPrimary (citable) accession number: A2ARI4
Secondary accession number(s): A2ARI3
, Q6PHA3, Q80T31, Q8BXS9
Entry historyi
Integrated into UniProtKB/Swiss-Prot: September 11, 2007
Last sequence update: February 20, 2007
Last modified: November 2, 2016
This is version 88 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. 7-transmembrane G-linked receptors
    List of 7-transmembrane G-linked receptor entries
  2. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  3. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.