Glial cell line-derived neurotrophic factor precursor

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P39905 (GDNF_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified January 25, 2012. Version 127. History...

Clusters with 100%, 90%, 50% identity |

Documents (6) |

Third-party data

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Names·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·Documents Customize order

Names and origin

Protein names

Recommended name:
Glial cell line-derived neurotrophic factor
Short name=hGDNF

Alternative name(s):
Astrocyte-derived trophic factor
Short name=ATF

Gene names

Name:

GDNF

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	211 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	Neurotrophic factor that enhances survival and morphological differentiation of dopaminergic neurons and increases their high-affinity dopamine uptake. Ref.1
Subunit structure	Homodimer; disulfide-linked. Ref.1 Ref.11
Subcellular location	Secreted Ref.10.
Tissue specificity	In the brain, predominantly expressed in the striatum with highest levels in the caudate and lowest in the putamen. Ref.2
Induction	By cAMP, 12-O-tetradecanoylphorbol-13-acetate (TPA) and FGF2. Ref.10
Involvement in disease	Defects in GDNF may be a cause of Hirschsprung disease type 3 (HSCR3) [MIM:613711]. In association with mutations of RET gene, defects in GDNF may be involved in Hirschsprung disease. This genetic disorder of neural crest development is characterized by the absence of intramural ganglion cells in the hindgut, often resulting in intestinal obstruction. Ref.13 Ref.14 Ref.15 Ref.17 Defects in GDNF are a cause of congenital central hypoventilation syndrome (CCHS) [MIM:209880]; also known as congenital failure of autonomic control or Ondine curse. CCHS is a rare disorder characterized by abnormal control of respiration in the absence of neuromuscular or lung disease, or an identifiable brain stem lesion. A deficiency in autonomic control of respiration results in inadequate or negligible ventilatory and arousal responses to hypercapnia and hypoxemia. Ref.16
Sequence similarities	Belongs to the TGF-beta family. GDNF subfamily.

Ontologies

Keywords
Cellular component	Secreted
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation Hirschsprung disease
Domain	Signal
Molecular function	Growth factor
PTM	Cleavage on pair of basic residues Disulfide bond Glycoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	adult locomotory behavior Traceable author statement. Source: BHF-UCL anti-apoptosis Traceable author statement. Source: ProtInc axon guidance Traceable author statement. Source: Reactome branching involved in ureteric bud morphogenesis Inferred from sequence or structural similarity. Source: UniProtKB enteric nervous system development Inferred from sequence or structural similarity. Source: UniProtKB mRNA stabilization Inferred from direct assay. Source: BHF-UCL negative regulation of neuron apoptosis Inferred from direct assay Ref.1. Source: UniProtKB neural crest cell migration Inferred from direct assay. Source: MGI peristalsis Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of branching involved in ureteric bud morphogenesis Inferred from direct assay. Source: UniProtKB positive regulation of dopamine secretion Traceable author statement. Source: BHF-UCL positive regulation of monooxygenase activity Inferred from direct assay. Source: BHF-UCL positive regulation of transcription from RNA polymerase II promoter Inferred from direct assay. Source: BHF-UCL positive regulation of ureteric bud formation Inferred from direct assay. Source: UniProtKB postganglionic parasympathetic nervous system development Inferred from sequence or structural similarity. Source: UniProtKB regulation of dopamine uptake Inferred from direct assay Ref.1. Source: UniProtKB signal transduction Traceable author statement. Source: ProtInc sympathetic nervous system development Inferred from sequence or structural similarity. Source: UniProtKB
Cellular component	extracellular region Inferred from direct assay Ref.10. Source: UniProtKB
Molecular function	growth factor activity Non-traceable author statement. Source: UniProtKB protein homodimerization activity Inferred from direct assay Ref.1 Ref.11. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 4 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P39905-1) 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: P39905-2) Also known as: ATF-1; HFK2-GDNF; The sequence of this isoform differs from the canonical sequence as follows: 25-51: GKRPPEAPAEDRSLGRRRAPFALSSDS → A

Isoform 3 (identifier: P39905-3) Also known as: HFK3-GDNF; The sequence of this isoform differs from the canonical sequence as follows: 1-1: M → MQSLPNSNGAAAGRDFKM

Isoform 4 (identifier: P39905-4) Also known as: HFK4-GDNF; The sequence of this isoform differs from the canonical sequence as follows: 1-1: M → MQSLPNSNGAAAGRDFKM 25-51: GKRPPEAPAEDRSLGRRRAPFALSSDS → A

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 19

Potential

Propeptide

20 – 75

By similarity

PRO_0000034004

Chain

78 – 211

134

Glial cell line-derived neurotrophic factor

PRO_0000034005

Amino acid modifications

Glycosylation

126

N-linked (GlcNAc...) Potential

Glycosylation

162

N-linked (GlcNAc...) Potential

Disulfide bond

Disulfide bond

Disulfide bond

Disulfide bond

Interchain Ref.1 Ref.11

Natural variations

Alternative sequence

M → MQSLPNSNGAAAGRDFKM in isoform 3 and isoform 4.

VSP_026368

Alternative sequence

25 – 51

GKRPP…LSSDS → A in isoform 2 and isoform 4.

VSP_006420

Natural variant

P → S in HSCR3; could be a polymorphism. Ref.15

VAR_009494

Natural variant

R → W in HSCR3 and CCHS; associated to a RET mutation; could be an extremely rare polymorphism. Ref.14 Ref.16
Corresponds to variant rs36119840 [ dbSNP | Ensembl ].

VAR_009495

Natural variant

150

D → N in HSCR3; could be a polymorphism. Ref.15

VAR_009496

Natural variant

154

T → S in HSCR3; sporadic form. Ref.13

VAR_009497

Natural variant

211

I → M in HSCR3. Ref.17

VAR_018152

Secondary structure

211

Helix Strand Turn

Details...

Sequences

Sequence		Length	Mass (Da)
Isoform 1 [UniParc]. Last modified February 1, 1995. Version 1. Checksum: A0D1EBF77FC82691 Show »	FASTA	211	23,720
10 20 30 40 50 60 MKLWDVVAVC LVLLHTASAF PLPAGKRPPE APAEDRSLGR RRAPFALSSD SNMPEDYPDQ 70 80 90 100 110 120 FDDVMDFIQA TIKRLKRSPD KQMAVLPRRE RNRQAAAANP ENSRGKGRRG QRGKNRGCVL 130 140 150 160 170 180 TAIHLNVTDL GLGYETKEEL IFRYCSGSCD AAETTYDKIL KNLSRNRRLV SDKVGQACCR 190 200 210 PIAFDDDLSF LDDNLVYHIL RKHSAKRCGC I « Hide
Isoform 2 (ATF-1) (HFK2-GDNF) [UniParc]. Checksum: 1988C50DA5EA1B10 Show »	FASTA	185	20,885
10 20 30 40 50 60 MKLWDVVAVC LVLLHTASAF PLPAANMPED YPDQFDDVMD FIQATIKRLK RSPDKQMAVL 70 80 90 100 110 120 PRRERNRQAA AANPENSRGK GRRGQRGKNR GCVLTAIHLN VTDLGLGYET KEELIFRYCS 130 140 150 160 170 180 GSCDAAETTY DKILKNLSRN RRLVSDKVGQ ACCRPIAFDD DLSFLDDNLV YHILRKHSAK RCGCI « Hide
Isoform 3 (HFK3-GDNF) [UniParc]. Checksum: 5BAAAC69FEDDBA4C Show »	FASTA	228	25,466
10 20 30 40 50 60 MQSLPNSNGA AAGRDFKMKL WDVVAVCLVL LHTASAFPLP AGKRPPEAPA EDRSLGRRRA 70 80 90 100 110 120 PFALSSDSNM PEDYPDQFDD VMDFIQATIK RLKRSPDKQM AVLPRRERNR QAAAANPENS 130 140 150 160 170 180 RGKGRRGQRG KNRGCVLTAI HLNVTDLGLG YETKEELIFR YCSGSCDAAE TTYDKILKNL 190 200 210 220 SRNRRLVSDK VGQACCRPIA FDDDLSFLDD NLVYHILRKH SAKRCGCI « Hide
Isoform 4 (HFK4-GDNF) [UniParc]. Checksum: 2CAFBC675D40CF2F Show »	FASTA	202	22,631
10 20 30 40 50 60 MQSLPNSNGA AAGRDFKMKL WDVVAVCLVL LHTASAFPLP AANMPEDYPD QFDDVMDFIQ 70 80 90 100 110 120 ATIKRLKRSP DKQMAVLPRR ERNRQAAAAN PENSRGKGRR GQRGKNRGCV LTAIHLNVTD 130 140 150 160 170 180 LGLGYETKEE LIFRYCSGSC DAAETTYDKI LKNLSRNRRL VSDKVGQACC RPIAFDDDLS 190 200 FLDDNLVYHI LRKHSAKRCG CI « Hide

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons." Lin L.-F.H., Doherty D.H., Lile J.D., Bektesh S., Collins F. Science 260:1130-1132(1993) [PubMed: 8493557] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, HOMODIMERIZATION, DISULFIDE BONDS.
[2]	"Multiple astrocyte transcripts encode nigral trophic factors in rat and human." Schaar D.G., Sieber B.-A., Sherwood A.C., Dean D., Mendoza G., Ramakrishnan L., Dreyfus C.F., Black I.B. Exp. Neurol. 130:387-393(1994) [PubMed: 7867768] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), TISSUE SPECIFICITY.
[3]	Zhang B., Feng Z., Zhou Y., Peng X., Yuan J., Qiang B. Submitted (AUG-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
[4]	"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)." Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B. Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[5]	"The DNA sequence and comparative analysis of human chromosome 5." Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S. Rubin E.M. Nature 431:268-274(2004) [PubMed: 15372022] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	Mural R.J., Istrail S., Sutton G.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. Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[8]	"Characterization of a promoter for the human glial cell line-derived neurotrophic factor gene." Baecker P.A., Lee W.H., Verity A.N., Eglen R.M., Johnson R.M. Brain Res. Mol. Brain Res. 69:209-222(1999) [PubMed: 10366742] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1-187 (ISOFORM 1). Tissue: Fetal kidney.
[9]	"The human GDNF gene promoter." Suter-Crazzolara C., Baecker P.A., Lee W.H., Johnson R.M., Unsicker K. Submitted (OCT-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1-88 (ISOFORM 2), NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-77, NUCLEOTIDE SEQUENCE [MRNA] OF 1-59 (ISOFORMS 3 AND 4). Tissue: Brain and Kidney.
[10]	"Analysis of the human GDNF gene reveals an inducible promoter, three exons, a triplet repeat within the 3'-UTR and alternative splice products." Grimm L., Holinski-Feder E., Teodoridis J., Scheffer B., Schindelhauer D., Meitinger T., Ueffing M. Hum. Mol. Genet. 7:1873-1886(1998) [PubMed: 9811930] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-50, SUBCELLULAR LOCATION, INDUCTION.
[11]	"Glial cell line-derived neurotrophic factor: selective reduction of the intermolecular disulfide linkage and characterization of its disulfide structure." Haniu M., Hui J., Young Y., Le J., Katta V., Lee R., Shimamoto G., Rohde M.F. Biochemistry 35:16799-16805(1996) [PubMed: 8988018] [Abstract] Cited for: PROTEIN SEQUENCE OF 87-122; 141-153; 173-184 AND 196-211, HOMODIMERIZATION, DISULFIDE BONDS.
[12]	"Mutations in Hirschsprung disease: when does a mutation contribute to the phenotype." Hofstra R.M.W., Osinga J., Buys C.H.C.M. Eur. J. Hum. Genet. 5:180-185(1997) [PubMed: 9359036] [Abstract] Cited for: REVIEW ON VARIANTS.
[13]	"De novo mutation of GDNF, ligand for the RET/GDNFR-alpha receptor complex, in Hirschsprung disease." Ivanchuk S.M., Myers S.M., Eng C., Mulligan L.M. Hum. Mol. Genet. 5:2023-2026(1996) [PubMed: 8968758] [Abstract] Cited for: VARIANT HSCR3 SER-154.
[14]	"Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient." Angrist M., Bolk S., Halushka M., Lapchak P.A., Chakravarti A. Nat. Genet. 14:341-344(1996) [PubMed: 8896568] [Abstract] Cited for: VARIANT HSCR3 TRP-93.
[15]	"Germline mutations of the RET ligand GDNF are not sufficient to cause Hirschsprung disease." Salomon R., Attie T., Pelet A., Bidaud C., Eng C., Amiel J., Sarnacki S., Goulet O., Ricour C., Nihoul-Fekete C., Munnich A., Lyonnet S. Nat. Genet. 14:345-347(1996) [PubMed: 8896569] [Abstract] Cited for: VARIANTS HSCR3 SER-21 AND ASN-150.
[16]	"Mutations of the RET-GDNF signaling pathway in Ondine's curse." Amiel J., Salomon R., Attie T., Pelet A., Trang H., Mokhtari M., Gaultier C., Munnich A., Lyonnet S. Am. J. Hum. Genet. 62:715-717(1998) [PubMed: 9497256] [Abstract] Cited for: VARIANT CCHS TRP-93.
[17]	"Pathogenesis of Hirschsprung's disease." Martucciello G., Ceccherini I., Lerone M., Jasonni V. J. Pediatr. Surg. 35:1017-1025(2000) [PubMed: 10917288] [Abstract] Cited for: VARIANT HSCR3 MET-211.
+	Additional computationally mapped references.

Web resources

R&D Systems' cytokine mini-reviews: GDNF

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

L19063, L19062 Genomic DNA. Translation: AAA67910.1.
AY052832 mRNA. Translation: AAL11017.1.
CR541923 mRNA. Translation: CAG46721.1.
AC008869 Genomic DNA. No translation available.
CH471119 Genomic DNA. Translation: EAW55963.1.
BC069119 mRNA. Translation: AAH69119.1.
BC069369 mRNA. Translation: AAH69369.1.
BC128108 mRNA. Translation: AAI28109.1.
BC128109 mRNA. Translation: AAI28110.1.
AF053748 mRNA. Translation: AAD43139.1.
AJ001896 Genomic DNA. Translation: CAA05074.1.
AJ001897 mRNA. Translation: CAA05075.1.
AJ001898 mRNA. Translation: CAA05076.1.
AJ001899 mRNA. Translation: CAA05077.1.
AJ001900 mRNA. Translation: CAA05078.1.
AF063586 Genomic DNA. Translation: AAC98782.1.

IPI

IPI00026858.
IPI00375525.
IPI00848254.
IPI00848296.

PIR

B37499.

RefSeq

NP_000505.1. NM_000514.3.
NP_001177397.1. NM_001190468.1.
NP_001177398.1. NM_001190469.1.
NP_954701.1. NM_199231.2.

UniGene

Hs.248114.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2V5E	X-ray	2.35	B	111-211	[»]
3FUB	X-ray	2.35	B/D	78-211	[»]

ProteinModelPortal

P39905.

SMR

P39905. Positions 109-211.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-59051N.

STRING

P39905.

Polymorphism databases

DMDM

729567.

Proteomic databases

PRIDE

P39905.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000326524; ENSP00000317145; ENSG00000168621.
ENST00000427982; ENSP00000409007; ENSG00000168621.

GeneID

2668.

KEGG

hsa:2668.

UCSC

uc003jkx.1. human.
uc003jky.1. human.

Organism-specific databases

CTD

2668.

GeneCards

GC05M037812.

H-InvDB

HIX0031958.

HGNC

HGNC:4232. GDNF.

HPA

CAB005210.

MIM

209880. phenotype.
600837. gene.
613711. phenotype.

neXtProt

NX_P39905.

Orphanet

388. Hirschsprung disease.
661. Ondine syndrome.

PharmGKB

PA28644.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG05740.

GeneTree

ENSGT00520000055559.

HOVERGEN

HBG106680.

InParanoid

P39905.

OMA

PENSRGK.

OrthoDB

EOG45DWQN.

PhylomeDB

P39905.

Enzyme and pathway databases

Pathway_Interaction_DB

ret_pathway. Signaling events regulated by Ret tyrosine kinase.

Reactome

REACT_111045. Developmental Biology.

Gene expression databases

ArrayExpress

P39905.

Bgee

P39905.

Genevestigator

P39905.

GermOnline

ENSG00000168621. Homo sapiens.

Family and domain databases

InterPro

IPR016649. GDNF.
IPR001839. TGF-b_C.
[Graphical view]

K05452.

Pfam

PF00019. TGF_beta. 1 hit.
[Graphical view]

PIRSF

PIRSF016238. GDNF. 1 hit.

SMART

SM00204. TGFB. 1 hit.
[Graphical view]

PROSITE

PS00250. TGF_BETA_1. False negative.
PS51362. TGF_BETA_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

NextBio

10524.

SOURCE

Search...

Entry information

Entry name

GDNF_HUMAN

Accession

Primary (citable) accession number: P39905
Secondary accession number(s): B7WPK7

Q9UP97

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1995
Last sequence update:	February 1, 1995
Last modified:	January 25, 2012
This is version 127 of the entry and version 1 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.

Relevant documents

Human chromosome 5

Human chromosome 5: entries, gene names and cross-references to MIM

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

SIMILARITY comments

Index of protein domains and families

Names·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·Documents

Preferred order of sections

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Alternative products

Sequence annotation (Features)

Molecule processing

Amino acid modifications

Natural variations

Secondary structure

Sequences

References

Web resources

Cross-references

Sequence databases

3D structure databases

Protein-protein interaction databases

Polymorphism databases

Proteomic databases

Protocols and materials databases

Genome annotation databases

Organism-specific databases

Phylogenomic databases

Enzyme and pathway databases

Gene expression databases

Family and domain databases

Other

Entry information

Relevant documents