P51460 (INSL3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Dipnotetrapodomorpha › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Boreoeutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	131 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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 component	Secreted
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Domain	Signal
Molecular function	Hormone
PTM	Cleavage on pair of basic residues Disulfide bond
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	adenylate 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_component	extracellular 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_function	insulin 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 key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 20

20

Ref.9

Peptide

21 – 55

35

Insulin-like 3 B chain

PRO_0000016140

Propeptide

58 – 104

47

C peptide like Potential

PRO_0000016141

Peptide

106 – 131

26

Insulin-like 3 A chain

PRO_0000016142

Amino acid modifications

Disulfide bond

34 ↔ 116

Interchain (between B and A chains) Ref.11 Ref.12

Disulfide bond

46 ↔ 129

Interchain (between B and A chains) Ref.11 Ref.12

Disulfide bond

115 ↔ 120

Ref.11 Ref.12

Natural variations

Alternative sequence

64 – 131

68

RELLQ…TLCPY → QRESHSVSQAGLKLLSSSNP PTLTFQSVGISDVSCYSGWR DDICSMGWWPTVISRWDLAC SPCPRPLTITATTVQLPPTL HATAASVAVPNKTC in isoform 2.

VSP_045526

Natural variant

24

1

A → G. Ref.17
Corresponds to variant rs186828508 [ dbSNP | Ensembl ].

VAR_013231

Natural variant

43

1

V → L. Ref.17

VAR_013232

Natural variant

49

1

P → S Could be a rare polymorphism; identified in a male with undermasculinised genitalia and intra-abdominal testes. Ref.17

VAR_013233

Natural variant

60

1

T → 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 variant

93

1

P → L in CRYPTO. Ref.14
Corresponds to variant rs104894697 [ dbSNP | Ensembl ].

VAR_013235

Natural variant

102

1

R → C in CRYPTO. Ref.16

VAR_013236

Natural variant

102

1

R → H. Ref.17

VAR_013237

Natural variant

110

1

N → K in CRYPTO. Ref.20

VAR_017122

Secondary structure

1

.

.

.

.

.

.

.

131

Helix Strand Turn

Details...

Helix

36 – 45

10

Helix

111 – 117

7

Helix

122 – 128

7

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified January 11, 2011. Version 2. Checksum: 94788D700524C12A	FASTA	131	14,502
	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
	Isoform 2 [UniParc]. Checksum: 0D5CAAD5B548BC7A	FASTA	157	16,872
	10 20 30 40 50 60 MDPRLPAWAL VLLGPALVFA LGPAPTPEMR EKLCGHHFVR ALVRVCGGPR WSTEARRPAT 70 80 90 100 110 120 GGDQRESHSV SQAGLKLLSS SNPPTLTFQS VGISDVSCYS GWRDDICSMG WWPTVISRWD 130 140 150 LACSPCPRPL TITATTVQLP PTLHATAASV AVPNKTC

References

	« Hide 'large scale' referencesShow '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. , 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. , 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. , 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.

PIR

B53024.

RefSeq

NP_001252516.1. NM_001265587.1.
NP_005534.2. NM_005543.3.

UniGene

Hs.37062.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2H8B	NMR	-	A	106-131	[»]
			B	25-55	[»]
2K6T	NMR	-	A	106-131	[»]
			B	25-55	[»]
2K6U	NMR	-	A	106-131	[»]
			B	25-49	[»]

ProteinModelPortal

P51460.

SMR

P51460. Positions 25-55, 106-131.

ModBase

Search...

MobiDB

Search...

Protein-protein interaction databases

BioGrid

109851. 1 interaction.

STRING

9606.ENSP00000321724.

Polymorphism databases

DMDM

317373369.

Proteomic databases

PaxDb

P51460.

PRIDE

P51460.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000317306; ENSP00000321724; ENSG00000248099. [P51460-1]
ENST00000379695; ENSP00000369017; ENSG00000248099. [P51460-2]

GeneID

3640.

KEGG

hsa:3640.

UCSC

uc002nhm.2. human. [P51460-1]
uc010ebf.2. human.

Organism-specific databases

CTD

3640.

GeneCards

GC19M017928.

H-InvDB

HIX0014900.

HGNC

HGNC:6086. INSL3.

HPA

HPA028615.

MIM

146738. gene.
219050. phenotype.

neXtProt

NX_P51460.

PharmGKB

PA29893.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG80279.

HOGENOM

HOG000113077.

HOVERGEN

HBG052133.

OMA

CYSGWRD.

OrthoDB

EOG7P5T43.

PhylomeDB

P51460.

TreeFam

TF106361.

Enzyme and pathway databases

Reactome

REACT_111102. Signal Transduction.

Gene expression databases

Bgee

P51460.

CleanEx

HS_INSL3.
HS_RLF.

Genevestigator

P51460.

Family and domain databases

Gene3D

1.10.100.10. 2 hits.

InterPro

IPR016179. Insulin-like.
IPR022353. Insulin_CS.
[Graphical view]

Pfam

PF00049. Insulin. 1 hit.
[Graphical view]

SMART

SM00078. IlGF. 1 hit.
[Graphical view]

SUPFAM

SSF56994. SSF56994. 2 hits.

PROSITE

PS00262. INSULIN. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

P51460.

GeneWiki

INSL3.

GenomeRNAi

3640.

NextBio

14247.

PRO

P51460.

SOURCE

Search...

Entry information

Entry name

INSL3_HUMAN

Accession

Primary (citable) accession number: P51460
Secondary accession number(s): B4DZ72 , 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 status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.