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Protein

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

Gene

LGR4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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 (By similarity).By similarity6 Publications

GO - Molecular functioni

  • G-protein coupled receptor activity Source: ProtInc
  • protein-hormone receptor activity Source: InterPro
  • transmembrane signaling receptor activity Source: UniProtKB

GO - Biological processi

Keywordsi

Molecular functionDevelopmental protein, G-protein coupled receptor, Receptor, Transducer
Biological processBiological rhythms, Differentiation, Immunity, Innate immunity, Spermatogenesis, Wnt signaling pathway

Enzyme and pathway databases

ReactomeiR-HSA-4641263 Regulation of FZD by ubiquitination
SIGNORiQ9BXB1

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
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 11

Organism-specific databases

EuPathDBiHostDB:ENSG00000205213.13
HGNCiHGNC:13299 LGR4
MIMi606666 gene
neXtProtiNX_Q9BXB1

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

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 – 620ExtracellularSequence analysisAdd BLAST24
Transmembranei621 – 641Helical; Name=3Sequence analysisAdd BLAST21
Topological domaini642 – 661CytoplasmicSequence analysisAdd BLAST20
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

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Involvement in diseasei

Osteoporosis (OSTEOP)1 Publication
Disease susceptibility may be associated with variations affecting the gene represented in this entry. A LGR4 nonsense mutation creating a stop codon after position 126 (c.376C>T) is strongly associated with low bone mineral density and osteoporotic fractures (PubMed:23644456). This mutation probably causes degradation of the transcript by nonsense-mediated decay (NMD). The c.376C>T mutation is also associated with electrolyte imbalance, late onset of menarche and reduced testosterone levels, as well as an increased risk of squamous cell carcinoma of the skin and biliary tract cancer (PubMed:23644456).1 Publication
Disease descriptionA systemic skeletal disorder characterized by decreased bone mass and deterioration of bone microarchitecture without alteration in the composition of bone. The result is fragile bones and an increased risk of fractures, even after minimal trauma. Osteoporosis is a chronic condition of multifactorial etiology and is usually clinically silent until a fracture occurs.
See also OMIM:166710

Organism-specific databases

DisGeNETi55366
MalaCardsiLGR4
MIMi166710 phenotype
615311 phenotype
OpenTargetsiENSG00000205213
PharmGKBiPA28893

Chemistry databases

GuidetoPHARMACOLOGYi147

Polymorphism and mutation databases

BioMutaiLGR4
DMDMi212286375

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 24Sequence analysisAdd BLAST24
ChainiPRO_000001279225 – 951Leucine-rich repeat-containing G-protein coupled receptor 4Add BLAST927

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi29 ↔ 35PROSITE-ProRule annotation1 Publication
Disulfide bondi33 ↔ 43PROSITE-ProRule annotation1 Publication
Glycosylationi68N-linked (GlcNAc...) asparagine1 Publication1
Glycosylationi199N-linked (GlcNAc...) asparagine1 Publication1
Glycosylationi294N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi314N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi339 ↔ 364PROSITE-ProRule annotation1 Publication
Disulfide bondi470 ↔ 522PROSITE-ProRule annotation1 Publication
Disulfide bondi471 ↔ 476PROSITE-ProRule annotation1 Publication
Glycosylationi505N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi618 ↔ 693PROSITE-ProRule annotation
Modified residuei920PhosphoserineCombined sources1

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein

Proteomic databases

EPDiQ9BXB1
MaxQBiQ9BXB1
PaxDbiQ9BXB1
PeptideAtlasiQ9BXB1
PRIDEiQ9BXB1
ProteomicsDBi79397

PTM databases

iPTMnetiQ9BXB1
PhosphoSitePlusiQ9BXB1

Expressioni

Tissue specificityi

Expressed in multiple steroidogenic tissues: placenta, ovary, testis and adrenal. Expressed also in spinal cord, thyroid, stomach, trachea, heart, pancreas, kidney, prostate and spleen.

Gene expression databases

BgeeiENSG00000205213 Expressed in 219 organ(s), highest expression level in liver
CleanExiHS_LGR4
ExpressionAtlasiQ9BXB1 baseline and differential
GenevisibleiQ9BXB1 HS

Organism-specific databases

HPAiHPA030267
HPA054350

Interactioni

Binary interactionsi

WithEntry#Exp.IntActNotes
ZNRF3Q9ULT62EBI-10965764,EBI-949772

Protein-protein interaction databases

BioGridi120644, 217 interactors
DIPiDIP-59894N
IntActiQ9BXB1, 3 interactors
STRINGi9606.ENSP00000368516

Structurei

Secondary structure

1951
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliQ9BXB1
SMRiQ9BXB1
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

Keywords - Domaini

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

Phylogenomic databases

eggNOGiKOG0619 Eukaryota
KOG2087 Eukaryota
COG4886 LUCA
GeneTreeiENSGT00760000119088
HOGENOMiHOG000231829
HOVERGENiHBG031675
InParanoidiQ9BXB1
KOiK04309
OMAiDGYWSDC
OrthoDBiEOG091G0QA0
PhylomeDBiQ9BXB1
TreeFamiTF316814

Family and domain databases

Gene3Di3.80.10.10, 1 hit
InterProiView protein in InterPro
IPR000276 GPCR_Rhodpsn
IPR017452 GPCR_Rhodpsn_7TM
IPR002131 Gphrmn_rcpt_fam
IPR001611 Leu-rich_rpt
IPR003591 Leu-rich_rpt_typical-subtyp
IPR032675 LRR_dom_sf
IPR000372 LRRNT
PfamiView protein in Pfam
PF00001 7tm_1, 1 hit
PF13855 LRR_8, 4 hits
PF01462 LRRNT, 1 hit
PRINTSiPR00373 GLYCHORMONER
PR00237 GPCRRHODOPSN
SMARTiView protein in SMART
SM00369 LRR_TYP, 15 hits
SM00013 LRRNT, 1 hit
PROSITEiView protein in PROSITE
PS50262 G_PROTEIN_RECEP_F1_2, 1 hit
PS51450 LRR, 15 hits

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

This entry has 2 described isoforms and 1 potential isoform that is computationally mapped.iShow all

Isoform 1 (identifier: Q9BXB1-1) [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
MPGPLGLLCF LALGLLGSAG 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 DDNSLTEVPV HPLSNLPTLQ ALTLALNKIS SIPDFAFTNL
210 220 230 240 250
SSLVVLHLHN NKIRSLSQHC FDGLDNLETL DLNYNNLGEF PQAIKALPSL
260 270 280 290 300
KELGFHSNSI SVIPDGAFDG NPLLRTIHLY DNPLSFVGNS AFHNLSDLHS
310 320 330 340 350
LVIRGASMVQ QFPNLTGTVH LESLTLTGTK ISSIPNNLCQ EQKMLRTLDL
360 370 380 390 400
SYNNIRDLPS FNGCHALEEI SLQRNQIYQI KEGTFQGLIS LRILDLSRNL
410 420 430 440 450
IHEIHSRAFA TLGPITNLDV SFNELTSFPT EGLNGLNQLK LVGNFKLKEA
460 470 480 490 500
LAAKDFVNLR SLSVPYAYQC CAFWGCDSYA NLNTEDNSLQ DHSVAQEKGT
510 520 530 540 550
ADAANVTSTL ENEEHSQIII HCTPSTGAFK PCEYLLGSWM IRLTVWFIFL
560 570 580 590 600
VALFFNLLVI LTTFASCTSL PSSKLFIGLI SVSNLFMGIY TGILTFLDAV
610 620 630 640 650
SWGRFAEFGI WWETGSGCKV AGFLAVFSSE SAIFLLMLAT VERSLSAKDI
660 670 680 690 700
MKNGKSNHLK QFRVAALLAF LGATVAGCFP LFHRGEYSAS PLCLPFPTGE
710 720 730 740 750
TPSLGFTVTL VLLNSLAFLL MAVIYTKLYC NLEKEDLSEN SQSSMIKHVA
760 770 780 790 800
WLIFTNCIFF CPVAFFSFAP LITAISISPE IMKSVTLIFF PLPACLNPVL
810 820 830 840 850
YVFFNPKFKE DWKLLKRRVT KKSGSVSVSI SSQGGCLEQD FYYDCGMYSH
860 870 880 890 900
LQGNLTVCDC CESFLLTKPV SCKHLIKSHS CPALAVASCQ RPEGYWSDCG
910 920 930 940 950
TQSAHSDYAD EEDSFVSDSS DQVQACGRAC FYQSRGFPLV RYAYNLPRVK

D
Length:951
Mass (Da):104,475
Last modified:July 22, 2008 - v2
Checksum:i42D48AE5F0BEB6B1
GO
Isoform 2 (identifier: Q9BXB1-2) [UniParc]FASTAAdd to basket

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

Show »
Length:927
Mass (Da):101,667
Checksum:i5046E961D4C693BB
GO

Computationally mapped potential isoform sequencesi

There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
E9PK51E9PK51_HUMAN
Leucine-rich repeat-containing G-pr...
LGR4
158Annotation score:

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti22S → G in AAH33039 (PubMed:15489334).Curated1
Sequence conflicti172P → H in AAH33039 (PubMed:15489334).Curated1
Sequence conflicti247L → R in AAF68989 (PubMed:11401528).Curated1
Sequence conflicti247L → R in AAK31153 (PubMed:11401528).Curated1
Sequence conflicti292F → S in AAF68989 (PubMed:11401528).Curated1
Sequence conflicti433L → P in AAF68989 (PubMed:11401528).Curated1
Sequence conflicti668L → S in AAF68989 (PubMed:11401528).Curated1
Sequence conflicti681L → I in AAH33039 (PubMed:15489334).Curated1

Polymorphismi

Genetic variations in LGR4 define the bone mineral density quantitative trait locus 17 (BMND17) [MIMi:615311]. Variance in bone mineral density influences bone mass, contributes to size determination in the general population, and is a susceptibility factor for osteoporotic fractures.1 Publication

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_044528215S → G1 PublicationCorresponds to variant dbSNP:rs2448010Ensembl.1
Natural variantiVAR_044529233N → S1 PublicationCorresponds to variant dbSNP:rs2472617Ensembl.1
Natural variantiVAR_044530480A → V. Corresponds to variant dbSNP:rs12284579Ensembl.1
Natural variantiVAR_044531684R → G. Corresponds to variant dbSNP:rs7125959Ensembl.1
Natural variantiVAR_044532709T → M. Corresponds to variant dbSNP:rs34717439Ensembl.1
Natural variantiVAR_044533844D → G. Corresponds to variant dbSNP:rs34804482Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_04713662 – 85Missing in isoform 2. 1 PublicationAdd BLAST24

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF346711, AF346709, AF346710 Genomic DNA Translation: AAK31153.1
AF257182 mRNA Translation: AAF68989.1
AC090597 Genomic DNA No translation available.
AC100771 Genomic DNA No translation available.
CH471064 Genomic DNA Translation: EAW68285.1
CH471064 Genomic DNA Translation: EAW68286.1
BC033039 mRNA Translation: AAH33039.1
CCDSiCCDS31449.1 [Q9BXB1-1]
CCDS86187.1 [Q9BXB1-2]
RefSeqiNP_001333361.1, NM_001346432.1 [Q9BXB1-2]
NP_060960.2, NM_018490.3 [Q9BXB1-1]
UniGeneiHs.502176

Genome annotation databases

EnsembliENST00000379214; ENSP00000368516; ENSG00000205213 [Q9BXB1-1]
ENST00000389858; ENSP00000374508; ENSG00000205213 [Q9BXB1-2]
GeneIDi55366
KEGGihsa:55366
UCSCiuc001mrj.5 human [Q9BXB1-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiLGR4_HUMAN
AccessioniPrimary (citable) accession number: Q9BXB1
Secondary accession number(s): A6NCH3
, G5E9B3, Q8N537, Q9NYD1
Entry historyiIntegrated into UniProtKB/Swiss-Prot: June 20, 2002
Last sequence update: July 22, 2008
Last modified: September 12, 2018
This is version 152 of the entry and version 2 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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