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P51460 (INSL3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 131. 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·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Insulin-like 3
Alternative name(s):
Leydig insulin-like peptide
Short name=Ley-I-L
Relaxin-like factor

Cleaved into the following 2 chains:

  1. Insulin-like 3 B chain
  2. Insulin-like 3 A chain
Gene names
Name:INSL3
Synonyms:RLF, RLNL
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length131 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Seems to play a role in testicular function. May be a trophic hormone with a role in testicular descent in fetal life. Is a ligand for LGR8 receptor.

Subunit structure

Heterodimer of a B chain and an A chain linked by two disulfide bonds. Ref.11 Ref.12

Subcellular location

Secreted.

Tissue specificity

Expressed in prenatal and postnatal Leydig cells. Found as well in the corpus luteum, trophoblast, fetal membranes and breast. Ref.3

Involvement in disease

Cryptorchidism (CRYPTO) [MIM:219050]: One of the most frequent congenital abnormalities in humans, involving 2-5% of male births. Cryptorchidism is associated with increased risk of infertility and testicular cancer.
Note: The disease may be caused by mutations affecting the gene represented in this entry. Ref.14 Ref.16 Ref.20

Sequence similarities

Belongs to the insulin family.

Sequence caution

The sequence CAA52017.1 differs from that shown. Reason: Erroneous gene model prediction.

Ontologies

Keywords
   Cellular componentSecreted
   Coding sequence diversityAlternative splicing
Polymorphism
   DiseaseDisease mutation
   DomainSignal
   Molecular functionHormone
   PTMCleavage on pair of basic residues
Disulfide bond
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processadenylate cyclase-inhibiting G-protein coupled receptor signaling pathway

Inferred from electronic annotation. Source: Ensembl

cell-cell signaling

Traceable author statement PubMed 8253799. Source: ProtInc

in utero embryonic development

Inferred from electronic annotation. Source: Ensembl

male gonad development

Inferred from electronic annotation. Source: Ensembl

negative regulation of apoptotic process

Inferred from electronic annotation. Source: Ensembl

negative regulation of cell proliferation

Inferred from electronic annotation. Source: Ensembl

oocyte maturation

Inferred from electronic annotation. Source: Ensembl

positive regulation of cAMP biosynthetic process

Inferred from electronic annotation. Source: Ensembl

positive regulation of cell proliferation

Inferred from electronic annotation. Source: Ensembl

spermatogenesis

Traceable author statement PubMed 8253799. Source: ProtInc

   Cellular_componentextracellular region

Traceable author statement. Source: Reactome

extracellular space

Inferred from electronic annotation. Source: Ensembl

perinuclear region of cytoplasm

Inferred from electronic annotation. Source: Ensembl

   Molecular_functioninsulin receptor binding

Traceable author statement PubMed 8253799. Source: ProtInc

protease binding

Inferred from physical interaction PubMed 20082125. Source: UniProtKB

receptor binding

Traceable author statement Ref.2. Source: ProtInc

Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: P51460-1)

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: P51460-2)

The sequence of this isoform differs from the canonical sequence as follows:
     64-131: RELLQWLERR...QQDLLTLCPY → QRESHSVSQA...ASVAVPNKTC
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2020 Ref.9
Peptide21 – 5535Insulin-like 3 B chain
PRO_0000016140
Propeptide58 – 10447C peptide like Potential
PRO_0000016141
Peptide106 – 13126Insulin-like 3 A chain
PRO_0000016142

Amino acid modifications

Disulfide bond34 ↔ 116Interchain (between B and A chains) Ref.11 Ref.12
Disulfide bond46 ↔ 129Interchain (between B and A chains) Ref.11 Ref.12
Disulfide bond115 ↔ 120 Ref.11 Ref.12

Natural variations

Alternative sequence64 – 13168RELLQ…TLCPY → QRESHSVSQAGLKLLSSSNP PTLTFQSVGISDVSCYSGWR DDICSMGWWPTVISRWDLAC SPCPRPLTITATTVQLPPTL HATAASVAVPNKTC in isoform 2.
VSP_045526
Natural variant241A → G. Ref.17
Corresponds to variant rs186828508 [ dbSNP | Ensembl ].
VAR_013231
Natural variant431V → L. Ref.17
VAR_013232
Natural variant491P → S Could be a rare polymorphism; identified in a male with undermasculinised genitalia and intra-abdominal testes. Ref.17
VAR_013233
Natural variant601T → A Common polymorphism. Ref.1 Ref.2 Ref.5 Ref.8 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17 Ref.18 Ref.19
Corresponds to variant rs6523 [ dbSNP | Ensembl ].
VAR_013234
Natural variant931P → L in CRYPTO. Ref.14
Corresponds to variant rs104894697 [ dbSNP | Ensembl ].
VAR_013235
Natural variant1021R → C in CRYPTO. Ref.16
VAR_013236
Natural variant1021R → H. Ref.17
VAR_013237
Natural variant1101N → K in CRYPTO. Ref.20
VAR_017122

Secondary structure

....... 131
Helix Strand Turn

Details...

Sequences

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

Last modified January 11, 2011. Version 2.
Checksum: 94788D700524C12A

FASTA13114,502
        10         20         30         40         50         60 
MDPRLPAWAL VLLGPALVFA LGPAPTPEMR EKLCGHHFVR ALVRVCGGPR WSTEARRPAT 

        70         80         90        100        110        120 
GGDRELLQWL ERRHLLHGLV ADSNLTLGPG LQPLPQTSHH HRHHRAAATN PARYCCLSGC 

       130 
TQQDLLTLCP Y 

« Hide

Isoform 2 [UniParc].

Checksum: 0D5CAAD5B548BC7A
Show »

FASTA15716,872

References

« Hide 'large scale' references
[1]"A human cDNA coding for the Leydig insulin-like peptide (Ley I-L)."
Burkhardt E., Adham I.M., Hobohm U., Murphy D., Sander C., Engel W.
Hum. Genet. 94:91-94(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT ALA-60.
Tissue: Testis.
[2]"Structural organization of the porcine and human genes coding for a Leydig cell-specific insulin-like peptide (LEY I-L) and chromosomal localization of the human gene (INSL3)."
Burkhardt E., Adham I.M., Brosig B., Gastmann A., Mattei M.-G., Engel W.
Genomics 20:13-19(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT ALA-60.
[3]"The human Leydig insulin-like (hLEY I-L) gene is expressed in the corpus luteum and trophoblast."
Tashima L.S., Hieber A.D., Greenwood F.C., Bryant-Greenwood G.D.
J. Clin. Endocrinol. Metab. 80:707-710(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY.
[4]"A novel human relaxin-like factor: evidence for the evolution of new hormonal functions?"
Lim H.N., Oakenfull E.A., Rajpert De Meyts E., Skakkebaek N.E., Hughes I.A., Hawkins J.R., Farr C.J.
Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), ALTERNATIVE SPLICING.
[5]"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 1), VARIANT ALA-60.
Tissue: Testis.
[6]"The DNA sequence and biology of human chromosome 19."
Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., Carrano A.V. expand/collapse author list , Caoile C., Chan Y.M., Christensen M., Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., Rubin E.M., Lucas S.M.
Nature 428:529-535(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[8]"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] (ISOFORM 1), VARIANT ALA-60.
Tissue: Brain.
[9]"Signal peptide prediction based on analysis of experimentally verified cleavage sites."
Zhang Z., Henzel W.J.
Protein Sci. 13:2819-2824(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 21-35.
[10]"INSL3/Leydig insulin-like peptide activates the LGR8 receptor important in testis descent."
Kumagai J., Hsu S.Y., Matsumi H., Roh J.-S., Fu P., Wade J.D., Bathgate R.A.D., Hsueh A.J.W.
J. Biol. Chem. 277:31283-31286(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH LGR8.
[11]"Solution structure and characterization of the LGR8 receptor binding surface of insulin-like peptide 3."
Rosengren K.J., Zhang S., Lin F., Daly N.L., Scott D.J., Hughes R.A., Bathgate R.A., Craik D.J., Wade J.D.
J. Biol. Chem. 281:28287-28295(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: STRUCTURE BY NMR OF 25-55 AND 106-131, SUBUNIT, DISULFIDE BONDS.
[12]"Solution structure of a conformationally restricted fully active derivative of the human relaxin-like factor."
Bullesbach E.E., Hass M.A., Jensen M.R., Hansen D.F., Kristensen S.M., Schwabe C., Led J.J.
Biochemistry 47:13308-13317(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: STRUCTURE BY NMR OF 25-55 AND 106-131, SUBUNIT, DISULFIDE BONDS.
[13]"Absence of mutations involving the INSL3 gene in human idiopathic cryptorchidism."
Krausz C., Quintana-Murci L., Fellous M., Siffroi J.P., McElreavey K.
Mol. Hum. Reprod. 6:298-302(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT ALA-60.
[14]"Insulin-like 3/relaxin-like factor gene mutations are associated with cryptorchidism."
Tomboc M., Lee P.A., Mitwally M.F., Schneck F.X., Bellinger M., Witchel S.F.
J. Clin. Endocrinol. Metab. 85:4013-4018(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT CRYPTO LEU-93, VARIANT ALA-60.
[15]"A common polymorphism in the human relaxin-like factor (RLF) gene: no relationship with cryptorchidism."
Koskimies P., Virtanen H., Lindstroem M., Kaleva M., Poutanen M., Huhtaniemi I., Toppari J.
Pediatr. Res. 47:538-541(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT ALA-60.
[16]"Novel insulin-like 3 (INSL3) gene mutation associated with human cryptorchidism."
Marin P., Ferlin A., Moro E., Rossi A., Bartoloni L., Rossato M., Foresta C.
Am. J. Med. Genet. 103:348-349(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT CRYPTO CYS-102, VARIANT ALA-60.
[17]"Genetic analysis of the INSL3 gene in patients with maldescent of the testis."
Lim H.N., Raipert-de Meyts E., Skakkebaek N.E., Hawkins J.R., Hughes I.A.
Eur. J. Endocrinol. 144:129-137(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS GLY-24; LEU-43; SER-49; ALA-60 AND HIS-102.
[18]"Different insulin-like 3 (INSL3) gene mutations not associated with human cryptorchidism."
Marin P., Ferlin A., Moro E., Garolla A., Foresta C.
J. Endocrinol. Invest. 24:RC13-RC15(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT ALA-60.
[19]"Ala/Thr60 variant of the Leydig insulin-like hormone is not associated with cryptorchidism in the Japanese population."
Takahashi I., Takahashi T., Komatsu M., Matsuda J., Takada G.
Pediatr. Int. 43:256-258(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT ALA-60.
[20]"A novel mutation of the insulin-like 3 gene in patients with cryptorchidism."
Canto P., Escudero I., Soederlund D., Nishimura E., Carranza-Lira S., Gutierrez J., Nava A., Mendez J.P.
J. Hum. Genet. 48:86-90(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT CRYPTO LYS-110.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
S72482 mRNA. Translation: AAB31371.1.
X73637 Genomic DNA. Translation: CAA52017.1. Sequence problems.
AY082014 mRNA. Translation: AAL92559.1.
AK302780 mRNA. Translation: BAG63984.1.
AC005952 Genomic DNA. No translation available.
AC007201 Genomic DNA. Translation: AAD22740.1.
CH471106 Genomic DNA. Translation: EAW84635.1.
BC032810 mRNA. Translation: AAH32810.1.
BC053345 mRNA. Translation: AAH53345.1.
BC071706 mRNA. Translation: AAH71706.1.
BC106721 mRNA. Translation: AAI06722.1.
BC106722 mRNA. Translation: AAI06723.1.
PIRB53024.
RefSeqNP_001252516.1. NM_001265587.1.
NP_005534.2. NM_005543.3.
UniGeneHs.37062.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2H8BNMR-A106-131[»]
B25-55[»]
2K6TNMR-A106-131[»]
B25-55[»]
2K6UNMR-A106-131[»]
B25-49[»]
ProteinModelPortalP51460.
SMRP51460. Positions 25-55, 106-131.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid109851. 1 interaction.
STRING9606.ENSP00000321724.

Polymorphism databases

DMDM317373369.

Proteomic databases

PaxDbP51460.
PRIDEP51460.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000317306; ENSP00000321724; ENSG00000248099. [P51460-1]
ENST00000379695; ENSP00000369017; ENSG00000248099. [P51460-2]
GeneID3640.
KEGGhsa:3640.
UCSCuc002nhm.2. human. [P51460-1]
uc010ebf.2. human.

Organism-specific databases

CTD3640.
GeneCardsGC19M017928.
H-InvDBHIX0014900.
HGNCHGNC:6086. INSL3.
HPAHPA028615.
MIM146738. gene.
219050. phenotype.
neXtProtNX_P51460.
PharmGKBPA29893.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG80279.
HOGENOMHOG000113077.
HOVERGENHBG052133.
OMACYSGWRD.
OrthoDBEOG7P5T43.
PhylomeDBP51460.
TreeFamTF106361.

Enzyme and pathway databases

ReactomeREACT_111102. Signal Transduction.

Gene expression databases

BgeeP51460.
CleanExHS_INSL3.
HS_RLF.
GenevestigatorP51460.

Family and domain databases

Gene3D1.10.100.10. 2 hits.
InterProIPR016179. Insulin-like.
IPR022353. Insulin_CS.
[Graphical view]
PfamPF00049. Insulin. 1 hit.
[Graphical view]
SMARTSM00078. IlGF. 1 hit.
[Graphical view]
SUPFAMSSF56994. SSF56994. 2 hits.
PROSITEPS00262. INSULIN. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceP51460.
GeneWikiINSL3.
GenomeRNAi3640.
NextBio14247.
PROP51460.
SOURCESearch...

Entry information

Entry nameINSL3_HUMAN
AccessionPrimary (citable) accession number: P51460
Secondary accession number(s): B4DZ72 expand/collapse secondary AC list , G3XAG0, Q3KPI5, Q3KPI6, Q6YNB5, Q9UEA2, Q9UPH6
Entry history
Integrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: January 11, 2011
Last modified: April 16, 2014
This is version 131 of the entry and version 2 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 19

Human chromosome 19: entries, gene names and cross-references to MIM