Reviewed, UniProtKB/Swiss-Prot P23560 (BDNF_HUMAN)

Names and origin

Protein names

Recommended name:
    Brain-derived neurotrophic factor
      Short name=BDNF
Alternative name(s):
    Abrineurin

Gene names

Name:

BDNF

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

Protein attributes

Sequence length	247 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	Promotes the survival of neuronal populations that are all located either in the central nervous system or directly connected to it. Major regulator of synaptic transmission and plasticity at adult synapses in many regions of the CNS. The versatility of BDNF is emphasized by its contribution to a range of adaptive neuronal responses including long-term potentiation (LTP), long-term depression (LTD), certain forms of short-term synaptic plasticity, as well as homeostatic regulation of intrinsic neuronal excitability. Ref.16
Subunit structure	Monomers and homodimers. Binds to NTRK2/TRKB.
Subcellular location	Secreted.
Post-translational modification	The propeptide is N-glycosylated and glycosulfated. Converted into mature BDNF by plasmin (PLG) By similarity.
Polymorphism	Variations in BDNF are associated with susceptibility to bulimia nervosa 2 (BULN2) [MIM:610269]. Several genes with an essential role in the regulation of eating behavior and body weight are considered candidates involved in the etiology of eating disorders (ED), but no relevant susceptibility genes with a major effect on anorexia nervosa (AN) or bulimia nervosa (BN) have been identified. BDNF has been implicated in the regulation of food intake and body weight in rodents. A strong association has been reported of the Met-66 allele of the Val-66-Met BDNF variant with restricting AN (ANR) and low minimum body mass index in Spanish patients. Met-66 variant is strongly associated to all ED subtypes (AN, ANR, binge-eating/purging AN and BN) in European patients. Another single nucleotide polymorphism located in the promoter region of the BDNF gene showed an effect on BN and late age at onset of weight loss. These are two variants associated with the pathophysiology of ED in different populations. These variants support a role for BDNF in the susceptibility to aberrant eating behaviors.
Involvement in disease	Defects in BDNF 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. CCHS is frequently complicated with neurocristopathies such as Hirschsprung disease that occurs in about 16% of CCHS cases. Ref.14 Haploinsufficiency of BDNF is strongly associated with Wilms tumor, aniridia, genitourinary anomalies, mental retardation, and obesity syndrome (WAGRO) [MIM:612469]. In a subgroup of individuals with the WAGR syndrome, obesity develops. The phenotype in this subset is associated with haploinsufficiency for the BDNF gene. Ref.20
Sequence similarities	Belongs to the NGF-beta family.

Ontologies

Keywords
Cellular component	Secreted
Coding sequence diversity	Polymorphism
Disease	Disease mutation
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
Gene Ontology (GO)
Cellular component	extracellular region Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	growth factor activity Ref.1 Traceable author statement. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
NTF3	P20783	1	EBI-1026003,EBI-1025994

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 18

18

Potential

Propeptide

19 – 128

110

Ref.8

PRO_0000019633

Chain

129 – 247

119

Brain-derived neurotrophic factor

PRO_0000019634

Sites

Site

57 – 58

2

Cleavage; by S1P

Amino acid modifications

Glycosylation

121

1

N-linked (GlcNAc...)

Disulfide bond

141 ↔ 208

Disulfide bond

186 ↔ 237

Disulfide bond

196 ↔ 239

Natural variations

Natural variant

2

1

T → I in CCHS. dbSNP rs8192466. Ref.14

VAR_018260

Natural variant

66

1

V → M Polymorphism that impairs localization to secretory granules or synapses; associated with poorer episodic memory; may have a protective effect in obsessive-compulsive disorder. dbSNP rs6265. Ref.16 Ref.12 Ref.15 Ref.17 Ref.18

VAR_004626

Natural variant

75

1

Q → H: dbSNP rs1048218.

VAR_011797

Natural variant

125

1

R → M: dbSNP rs1048220.

VAR_011798

Natural variant

127

1

R → L: dbSNP rs1048221.

VAR_011799

Experimental info

Mutagenesis

54

1

R → A: Abolishes processing by S1P. Ref.11

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

247

Helix Strand Turn

Details...

Beta strand

138 – 141

4

Beta strand

143 – 149

7

Helix

150 – 153

4

Beta strand

155 – 158

4

Beta strand

163 – 166

4

Beta strand

168 – 171

4

Beta strand

173 – 178

6

Beta strand

180 – 186

7

Helix

191 – 193

3

Turn

201 – 203

3

Beta strand

204 – 220

17

Beta strand

226 – 243

18

Sequences

	Sequence		Length	Mass (Da)
	P23560-1 [UniParc]. Last modified November 1, 1991. Version 1. Checksum: 0A60488254722A99	FASTA	247	27,818
	10 20 30 40 50 60 MTILFLTMVI SYFGCMKAAP MKEANIRGQG GLAYPGVRTH GTLESVNGPK AGSRGLTSLA 70 80 90 100 110 120 DTFEHVIEEL LDEDQKVRPN EENNKDADLY TSRVMLSSQV PLEPPLLFLL EEYKNYLDAA 130 140 150 160 170 180 NMSMRVRRHS DPARRGELSV CDSISEWVTA ADKKTAVDMS GGTVTVLEKV PVSKGQLKQY 190 200 210 220 230 240 FYETKCNPMG YTKEGCRGID KRHWNSQCRT TQSYVRALTM DSKKRIGWRF IRIDTSCVCT LTIKRGR

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Molecular cloning of a human gene that is a member of the nerve growth factor family." Jones K.R., Reichardt L.F. Proc. Natl. Acad. Sci. U.S.A. 87:8060-8064(1990) [PubMed: 2236018] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[2]	"Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations." Maisonpierre P.C., le Beau M.M., Espinosa R. III, Ip N.Y., Belluscio L., de la Monte S.M., Squinto S., Furth M.E., Yancopoulos G.D. Genomics 10:558-568(1991) [PubMed: 1889806] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
[3]	"Characterization of the 5'-flanking region of the human brain-derived neurotrophic factor gene." Shintani A., Ono Y., Kaisho Y., Igarashi K. Biochem. Biophys. Res. Commun. 182:325-332(1992) [PubMed: 1339267] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[4]	"A cDNA clone of human brain-derived neurotrophic factor (HUMBDNFD)." Cheng Y., Gu J. Submitted (MAY-1995) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[5]	Wu J., Zhang B., Zhou Y., Peng X., Yuan J., Qiang B. Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[6]	"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]. Tissue: Brain.
[7]	"Evolutionary studies of the nerve growth factor family reveal a novel member abundantly expressed in Xenopus ovary." Hallboeoek F., Ibanez C.F., Persson H. Neuron 6:845-858(1991) [PubMed: 2025430] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 185-227. Tissue: Leukocyte.
[8]	"Purification and identification of brain-derived neurotrophic factor from human serum." Rosenfeld R.D., Zeni L., Haniu M., Talvenheimo J., Radka S.F., Bennett L., Miller J.A., Welcher A.A. Protein Expr. Purif. 6:465-471(1995) [PubMed: 8527932] [Abstract] Cited for: PROTEIN SEQUENCE OF 129-144. Tissue: Serum.
[9]	"Molecular phylogenetics and the origins of placental mammals." Murphy W.J., Eizirik E., Johnson W.E., Zhang Y.-P., Ryder O.A., O'Brien S.J. Nature 409:614-618(2001) [PubMed: 11214319] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 12-197.
[10]	"Structure of the brain-derived neurotrophic factor/neurotrophin 3 heterodimer." Robinson R.C., Radziejewski C., Stuart D.I., Jones E.Y. Biochemistry 34:4139-4146(1995) [PubMed: 7703225] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS).
[11]	"Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor." Mowla S.J., Farhadi H.F., Pareek S., Atwal J.K., Morris S.J., Seidah N.G., Murphy R.A. J. Biol. Chem. 276:12660-12666(2001) [PubMed: 11152678] [Abstract] Cited for: CHARACTERIZATION, MUTAGENESIS OF ARG-54.
[12]	"Characterization of single-nucleotide polymorphisms in coding regions of human genes." Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., Lander E.S. Nat. Genet. 22:231-238(1999) [PubMed: 10391209] [Abstract] Cited for: VARIANT MET-66.
[13]	Erratum Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., Lander E.S. Nat. Genet. 23:373-373(1999)
[14]	"Idiopathic congenital central hypoventilation syndrome: evaluation of brain-derived neurotrophic factor genomic DNA sequence variation." Weese-Mayer D.E., Bolk S., Silvestri J.M., Chakravarti A. Am. J. Med. Genet. 107:306-310(2002) [PubMed: 11840487] [Abstract] Cited for: VARIANT CCHS ILE-2.
[15]	"Sequence variants of the brain-derived neurotrophic factor (BDNF) gene are strongly associated with obsessive-compulsive disorder." Hall D., Dhilla A., Charalambous A., Gogos J.A., Karayiorgou M. Am. J. Hum. Genet. 73:370-376(2003) [PubMed: 12836135] [Abstract] Cited for: ROLE OF VARIANT MET-66 IN OBSESSIVE-COMPULSIVE DISORDER.
[16]	"The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function." Egan M.F., Kojima M., Callicott J.H., Goldberg T.E., Kolachana B.S., Bertolino A., Zaitsev E., Gold B., Goldman D., Dean M., Lu B., Weinberger D.R. Cell 112:257-269(2003) [PubMed: 12553913] [Abstract] Cited for: CHARACTERIZATION OF VARIANT MET-66, ROLE IN EPISODIC MEMORY.
[17]	"Molecular analysis of congenital central hypoventilation syndrome." Sasaki A., Kanai M., Kijima K., Akaba K., Hashimoto M., Hasegawa H., Otaki S., Koizumi T., Kusuda S., Ogawa Y., Tuchiya K., Yamamoto W., Nakamura T., Hayasaka K. Hum. Genet. 114:22-26(2003) [PubMed: 14566559] [Abstract] Cited for: VARIANT MET-66.
[18]	"Met66 in the brain-derived neurotrophic factor (BDNF) precursor is associated with anorexia nervosa restrictive type." Ribases M., Gratacos M., Armengol L., de Cid R., Badia A., Jimenez L., Solano R., Vallejo J., Fernandez F., Estivill X. Mol. Psychiatry 8:745-751(2003) [PubMed: 12888803] [Abstract] Cited for: ASSOCIATION OF VARIANT MET-66 WITH ANR.
[19]	"Association of BDNF with anorexia, bulimia and age of onset of weight loss in six European populations." Ribases M., Gratacos M., Fernandez-Aranda F., Bellodi L., Boni C., Anderluh M., Cavallini M.C., Cellini E., Di Bella D., Erzegovesi S., Foulon C., Gabrovsek M., Gorwood P., Hebebrand J., Hinney A., Holliday J., Hu X., Karwautz A. , Kipman A., Komel R., Nacmias B., Remschmidt H., Ricca V., Sorbi S., Wagner G., Treasure J., Collier D.A., Estivill X. Hum. Mol. Genet. 13:1205-1212(2004) [PubMed: 15115760] [Abstract] Cited for: POLYMORPHISM, ASSOCIATION WITH BULIMIA NERVOSA.
[20]	"Brain-derived neurotrophic factor and obesity in the WAGR syndrome." Han J.C., Liu Q.-R., Jones M., Levinn R.L., Menzie C.M., Jefferson-George K.S., Adler-Wailes D.C., Sanford E.L., Lacbawan F.L., Uhl G.R., Rennert O.M., Yanovski J.A. N. Engl. J. Med. 359:918-927(2008) [PubMed: 18753648] [Abstract] Cited for: INVOLVEMENT IN WAGRO SYNDROME.
[21]	Erratum Han J.C., Liu Q.-R., Jones M., Levinn R.L., Menzie C.M., Jefferson-George K.S., Adler-Wailes D.C., Sanford E.L., Lacbawan F.L., Uhl G.R., Rennert O.M., Yanovski J.A. N. Engl. J. Med. 359:1414-1414(2008)
+	Additional computationally mapped references.

Web resources

Wikipedia

BDNF entry

Cross-references

Sequence databases

EMBLGenBankDDBJ

M37762 Genomic DNA. Translation: AAA51820.1.
M61176 mRNA. Translation: AAA69805.2.
M61181 Genomic DNA. Translation: AAA96140.1.
X60201 mRNA. Translation: CAA42761.1.
X91251 mRNA. Translation: CAA62632.1.
AF400438 mRNA. Translation: AAK92487.1.
BC029795 mRNA. Translation: AAH29795.1.
AY011481 Genomic DNA. Translation: AAG47514.1.

IPI

IPI00012058.

PIR

A40304. B36208.

RefSeq

NP_001137277.1.
NP_001137278.1.
NP_001137279.1.
NP_001137280.1.
NP_001137283.1.
NP_001137284.1.
NP_001137285.1.
NP_001137286.1.
NP_001137287.1.
NP_001137288.1.
NP_001700.2.
NP_733928.1.
NP_733929.1.
NP_733931.1.

UniGene

Hs.502182

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1B8M	X-ray	2.75	A	129-247	[»]
1BND	X-ray	2.30	A	129-247	[»]

ModBase

Search...

Protein-protein interaction databases

DIP

DIP:5719N.

IntAct

P23560. 1 interaction.

PTM databases

PhosphoSite

P23560.

Proteomic databases

PRIDE

P23560.

Genome annotation databases

Ensembl

ENSG00000176697. Homo sapiens. [Contig view]

GeneID

627.

KEGG

hsa:627.

UCSC

uc001mrs.1. human.

Organism-specific databases

GeneCards

GC11M027633.

H-InvDB

HIX0009519.

HGNC

HGNC:1033. BDNF.

HPA

CAB009564.

MIM

113505. gene.
209880. phenotype.
610269. phenotype.
612469. phenotype.

Orphanet

661. Ondine syndrome.

PharmGKB

PA25335.

GenAtlas

Search...

Phylogenomic databases

HOVERGEN

P23560.

Enzyme and pathway databases

Pathway_Interaction_DB

trkrpathway. Neurotrophic factor-mediated Trk receptor signaling.
p75ntrpathway. p75(NTR)-mediated signaling.

Gene expression databases

ArrayExpress

P23560.

Bgee

P23560.

CleanEx

HS_BDNF.

GermOnline

ENSG00000176697. Homo sapiens.

Family and domain databases

InterPro

IPR002072. Nerve_growth_factor-rel.
IPR019846. Nerve_growth_factor_CS.
[Graphical view]

PANTHER

PTHR11589. NGF. 1 hit.

Pfam

PF00243. NGF. 1 hit.
[Graphical view]

PIRSF

PIRSF001789. NGF. 1 hit.

PRINTS

PR00268. NGF.

ProDom

PD002052. NGF. 1 hit.
[Graphical view] [Entries sharing at least one domain]

SMART

SM00140. NGF. 1 hit.
[Graphical view]

PROSITE

PS00248. NGF_1. 1 hit.
PS50270. NGF_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

2530.

PMAP-CutDB

P23560.

SOURCE

Search...

Entry information

Entry name

BDNF_HUMAN

Accession

Primary (citable) accession number: P23560
Secondary accession number(s): Q9BYY7, Q9UC24

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1991
Last sequence update:	November 1, 1991
Last modified:	July 7, 2009
This is version 110 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)