Reviewed, UniProtKB/Swiss-Prot P39905 (GDNF_HUMAN)

Names and origin

Protein names

Recommended name:
    Glial cell line-derived neurotrophic factor
Alternative name(s):
    Astrocyte-derived trophic factor
      Short name=ATF
      Short name=hGDNF

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.
Subunit structure	Homodimer; disulfide-linked.
Subcellular location	Secreted.
Tissue specificity	In the brain, predominantly expressed in the striatum with highest levels in the caudate and lowest in the putamen.
Induction	By cAMP, tetradecanoyl 12-phorbol acetate and fibroblast growth factor 2.
Involvement in disease	Defects in GDNF may be a cause of Hirschsprung disease (HSCR) [MIM:142623]. 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. 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.
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 Glycoprotein
Technical term	Direct protein sequencing
Gene Ontology (GO)
Biological process	adult locomotory behavior Traceable author statement. Source: UniProtKB anti-apoptosis Traceable author statement. Source: ProtInc mRNA stabilization Inferred from direct assay. Source: UniProtKB negative regulation of neuron apoptosis Ref.1 Inferred from direct assay. Source: UniProtKB neural crest cell migration Inferred from direct assay. Source: MGI neurite development Inferred from direct assay. Source: MGI positive regulation of dopamine secretion Traceable author statement. Source: UniProtKB positive regulation of monooxygenase activity Inferred from direct assay. Source: UniProtKB positive regulation of specific transcription from RNA polymerase II promoter Inferred from direct assay. Source: UniProtKB regulation of dopamine uptake Ref.1 Inferred from direct assay. Source: UniProtKB signal transduction Traceable author statement. Source: ProtInc
Cellular component	extracellular region Ref.8 Inferred from direct assay. Source: UniProtKB
Molecular function	growth factor activity Non-traceable author statement. Source: UniProtKB protein homodimerization activity Ref.1 Ref.9 Inferred from direct assay. 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	19	Potential
	Propeptide	20 – 75	56	By similarity		PRO_0000034004
	Chain	78 – 211	134	Glial cell line-derived neurotrophic factor		PRO_0000034005
Amino acid modifications
	Glycosylation	126	1	N-linked (GlcNAc...) Potential
	Glycosylation	162	1	N-linked (GlcNAc...) Potential
	Disulfide bond	118 ↔ 179
	Disulfide bond	145 ↔ 208
	Disulfide bond	149 ↔ 210
	Disulfide bond	178		Interchain
Natural variations
	Alternative sequence	1	1	M → MQSLPNSNGAAAGRDFKM in isoform 3 and isoform 4.		VSP_026368
	Alternative sequence	25 – 51	27	GKRPP…LSSDS → A in isoform 2 and isoform 4.		VSP_006420
	Natural variant	21	1	P → S in HSCR; could be a polymorphism.		VAR_009494
	Natural variant	93	1	R → W in HSCR and CCHS; associated to a RET mutation; could be an extremely rare polymorphism.		VAR_009495
	Natural variant	150	1	D → N in HSCR; could be a polymorphism.		VAR_009496
	Natural variant	154	1	T → S in HSCR; sporadic form.		VAR_009497
	Natural variant	211	1	I → M in HSCR.		VAR_018152

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified February 1, 1995. Version 1. Checksum: A0D1EBF77FC82691	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
	Isoform 2 (ATF-1) (HFK2-GDNF) [UniParc]. Checksum: 1988C50DA5EA1B10		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
	Isoform 3 (HFK3-GDNF) [UniParc]. Checksum: 5BAAAC69FEDDBA4C		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
	Isoform 4 (HFK4-GDNF) [UniParc]. Checksum: 2CAFBC675D40CF2F		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

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 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).
[6]	"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.
[7]	"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.
[8]	"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.
[9]	"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.
[10]	"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.
[11]	"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 HSCR SER-154.
[12]	"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 HSCR TRP-93.
[13]	"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 HSCR SER-21 AND ASN-150.
[14]	"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.
[15]	"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 HSCR MET-211.
+	Additional computationally mapped references.

Web resources

R&D Systems' cytokine mini-reviews: GDNF

GeneReviews

Cross-references

Sequence databases
EMBLGenBankDDBJ	L19063, L19062 Genomic DNA. Translation: AAA67910.1. AY052832 mRNA. Translation: AAL11017.1. CR541923 mRNA. Translation: CAG46721.1. 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.
PIR	B37499.
RefSeq	NP_000505.1. NP_954701.1. NP_954704.1.
UniGene	Hs.248114
3D structure databases
HSSP	HSSP built from PDB template 1AGQ based on UniProtKB Q07731.
SMR	P39905. Positions 117-211.
ModBase	Search...
PTM databases
PhosphoSite	P39905.
Genome annotation databases
Ensembl	ENSG00000168621. Homo sapiens. [Contig view]
GeneID	2668.
KEGG	hsa:2668.
Organism-specific databases
H-InvDB	HIX0031958.
HGNC	HGNC:4232. GDNF.
HPA	CAB005210.
MIM	142623. phenotype. 209880. phenotype. 600837. gene.
Orphanet	388. Hirschsprung disease. 661. Ondine syndrome.
PharmGKB	PA28644.
GenAtlas	Search...
GeneCards	Search...
Phylogenomic databases
HOGENOM	P39905.
HOVERGEN	P39905.
Gene expression databases
ArrayExpress	P39905.
GermOnline	ENSG00000168621. Homo sapiens.
Family and domain databases
InterPro	IPR016649. GDNF. IPR002400. GF_cysknot. IPR001839. TGFb. [Graphical view]
Pfam	PF00019. TGF_beta. 1 hit. [Graphical view]
PIRSF	PIRSF016238. GDNF. 1 hit.
PRINTS	PR00438. GFCYSKNOT.
ProDom	PD000357. TGFb. 1 hit. [Graphical view] [Entries sharing at least one domain]
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 Resources
NextBio	10524.
SOURCE	Search...

Entry information

Entry name

GDNF_HUMAN

Accession

Primary (citable) accession number: P39905
Secondary accession number(s): O95448 , O95449, O95986, Q6FH33, Q96L44, Q9UD32, Q9UD33, Q9UMV2, Q9UP67, Q9UP97

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1995
Last sequence update:	February 1, 1995
Last modified:	November 25, 2008
This is version 93 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)