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Protein

Glial cell line-derived neurotrophic factor

Gene

GDNF

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Neurotrophic factor that enhances survival and morphological differentiation of dopaminergic neurons and increases their high-affinity dopamine uptake.1 Publication

GO - Molecular functioni

  • protein homodimerization activity Source: UniProtKB
  • Ras guanyl-nucleotide exchange factor activity Source: Reactome
  • receptor binding Source: ProtInc

GO - Biological processi

  • adult locomotory behavior Source: BHF-UCL
  • branching involved in ureteric bud morphogenesis Source: UniProtKB
  • enteric nervous system development Source: UniProtKB
  • MAPK cascade Source: Reactome
  • mesenchymal to epithelial transition involved in metanephros morphogenesis Source: Ensembl
  • metanephros development Source: UniProtKB
  • mRNA stabilization Source: BHF-UCL
  • negative regulation of apoptotic process Source: ProtInc
  • negative regulation of extrinsic apoptotic signaling pathway in absence of ligand Source: UniProtKB
  • negative regulation of neuron apoptotic process Source: UniProtKB
  • nervous system development Source: ProtInc
  • neural crest cell migration Source: MGI
  • neuron projection development Source: MGI
  • organ induction Source: Ensembl
  • peristalsis Source: UniProtKB
  • positive regulation of branching involved in ureteric bud morphogenesis Source: UniProtKB
  • positive regulation of cell differentiation Source: MGI
  • positive regulation of cell proliferation Source: MGI
  • positive regulation of dopamine secretion Source: BHF-UCL
  • positive regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis Source: Ensembl
  • positive regulation of monooxygenase activity Source: BHF-UCL
  • positive regulation of transcription from RNA polymerase II promoter Source: BHF-UCL
  • positive regulation of ureteric bud formation Source: UniProtKB
  • postganglionic parasympathetic fiber development Source: UniProtKB
  • postsynaptic membrane organization Source: Ensembl
  • regulation of dopamine uptake involved in synaptic transmission Source: UniProtKB
  • regulation of gene expression Source: MGI
  • regulation of morphogenesis of a branching structure Source: UniProtKB
  • regulation of stem cell differentiation Source: ParkinsonsUK-UCL
  • signal transduction Source: ProtInc
  • sympathetic nervous system development Source: UniProtKB
  • ureteric bud formation Source: Ensembl
Complete GO annotation...

Keywords - Molecular functioni

Growth factor

Enzyme and pathway databases

ReactomeiR-HSA-419037. NCAM1 interactions.
R-HSA-5673001. RAF/MAP kinase cascade.
SignaLinkiP39905.
SIGNORiP39905.

Names & Taxonomyi

Protein namesi
Recommended name:
Glial cell line-derived neurotrophic factor
Short name:
hGDNF
Alternative name(s):
Astrocyte-derived trophic factor
Short name:
ATF
Gene namesi
Name:GDNF
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 5

Organism-specific databases

HGNCiHGNC:4232. GDNF.

Subcellular locationi

GO - Cellular componenti

  • extracellular region Source: UniProtKB
  • intracellular Source: GOC
Complete GO annotation...

Keywords - Cellular componenti

Secreted

Pathology & Biotechi

Involvement in diseasei

Hirschsprung disease 3 (HSCR3)4 Publications
The disease may be caused by mutations affecting the gene represented in this entry.
Disease descriptionA disorder of neural crest development characterized by absence of enteric ganglia along a variable length of the intestine. It is the most common cause of congenital intestinal obstruction. Early symptoms range from complete acute neonatal obstruction, characterized by vomiting, abdominal distention and failure to pass stool, to chronic constipation in the older child.
See also OMIM:613711
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti21 – 211P → S in HSCR3; unknown pathological significance. 1 Publication
Corresponds to variant rs777451569 [ dbSNP | Ensembl ].
VAR_009494
Natural varianti93 – 931R → W in HSCR3 and CCHS; associated to a RET mutation; unknown pathological significance. 2 Publications
Corresponds to variant rs36119840 [ dbSNP | Ensembl ].
VAR_009495
Natural varianti150 – 1501D → N in HSCR3; unknown pathological significance. 1 Publication
Corresponds to variant rs76466003 [ dbSNP | Ensembl ].
VAR_009496
Natural varianti154 – 1541T → S in HSCR3; sporadic form. 1 Publication
Corresponds to variant rs104893891 [ dbSNP | Ensembl ].
VAR_009497
Natural varianti211 – 2111I → M in HSCR3. 1 Publication
Corresponds to variant rs121918536 [ dbSNP | Ensembl ].
VAR_018152
Congenital central hypoventilation syndrome (CCHS)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionRare 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.
See also OMIM:209880
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti93 – 931R → W in HSCR3 and CCHS; associated to a RET mutation; unknown pathological significance. 2 Publications
Corresponds to variant rs36119840 [ dbSNP | Ensembl ].
VAR_009495

Keywords - Diseasei

Disease mutation, Hirschsprung disease

Organism-specific databases

MalaCardsiGDNF.
MIMi209880. phenotype.
613711. phenotype.
Orphaneti388. Hirschsprung disease.
PharmGKBiPA28644.

Polymorphism and mutation databases

BioMutaiGDNF.
DMDMi729567.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 1919Sequence analysisAdd
BLAST
Propeptidei20 – 7556By similarityPRO_0000034004Add
BLAST
Chaini78 – 211134Glial cell line-derived neurotrophic factorPRO_0000034005Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Disulfide bondi118 ↔ 1791 Publication
Glycosylationi126 – 1261N-linked (GlcNAc...)1 Publication
Disulfide bondi145 ↔ 2081 Publication
Disulfide bondi149 ↔ 2101 Publication
Glycosylationi162 – 1621N-linked (GlcNAc...)Sequence analysis
Disulfide bondi178 – 178Interchain

Keywords - PTMi

Cleavage on pair of basic residues, Disulfide bond, Glycoprotein

Proteomic databases

PaxDbiP39905.
PRIDEiP39905.

PTM databases

iPTMnetiP39905.
PhosphoSiteiP39905.

Expressioni

Tissue specificityi

In the brain, predominantly expressed in the striatum with highest levels in the caudate and lowest in the putamen. Isoform 2 is absent from most tissues except for low levels in intestine and kidney. Highest expression of isoform 3 is found in pancreatic islets. Isoform 5 is expressed at very low levels in putamen, nucleus accumbens, prefrontal cortex, amygdala, hypothalamus and intestine. Isoform 3 is up-regulated in the middle temporal gyrus of Alzheimer disease patients while isoform 2 shows no change.2 Publications

Inductioni

By cAMP, 12-O-tetradecanoylphorbol-13-acetate (TPA) and FGF2.1 Publication

Gene expression databases

BgeeiENSG00000168621.
ExpressionAtlasiP39905. baseline and differential.
GenevisibleiP39905. HS.

Organism-specific databases

HPAiCAB005210.

Interactioni

Subunit structurei

Homodimer; disulfide-linked.3 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
AGTRAPQ6RW133EBI-10207709,EBI-741181

GO - Molecular functioni

  • protein homodimerization activity Source: UniProtKB
  • receptor binding Source: ProtInc

Protein-protein interaction databases

BioGridi108936. 13 interactions.
DIPiDIP-59051N.
IntActiP39905. 2 interactions.
STRINGi9606.ENSP00000409007.

Structurei

Secondary structure

1
211
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Turni114 – 1174Combined sources
Beta strandi119 – 1268Combined sources
Helixi127 – 1304Combined sources
Beta strandi139 – 1479Combined sources
Helixi155 – 16511Combined sources
Beta strandi168 – 1736Combined sources
Beta strandi178 – 1847Combined sources
Beta strandi188 – 1914Combined sources
Beta strandi197 – 2004Combined sources
Beta strandi204 – 2118Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
2V5EX-ray2.35B111-211[»]
3FUBX-ray2.35B/D78-211[»]
4UX8electron microscopy24.00D/F78-211[»]
ProteinModelPortaliP39905.
SMRiP39905. Positions 109-211.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP39905.

Family & Domainsi

Sequence similaritiesi

Belongs to the TGF-beta family. GDNF subfamily.Curated

Keywords - Domaini

Signal

Phylogenomic databases

eggNOGiENOG410IGT5. Eukaryota.
ENOG4111I3D. LUCA.
GeneTreeiENSGT00520000055559.
HOVERGENiHBG106680.
InParanoidiP39905.
KOiK05452.
OMAiAKRCGCV.
OrthoDBiEOG091G0P1K.
PhylomeDBiP39905.
TreeFamiTF332366.

Family and domain databases

Gene3Di2.10.90.10. 1 hit.
InterProiIPR029034. Cystine-knot_cytokine.
IPR016649. GDNF.
IPR001839. TGF-b_C.
[Graphical view]
PfamiPF00019. TGF_beta. 1 hit.
[Graphical view]
PIRSFiPIRSF016238. GDNF. 1 hit.
SMARTiSM00204. TGFB. 1 hit.
[Graphical view]
SUPFAMiSSF57501. SSF57501. 1 hit.
PROSITEiPS51362. TGF_BETA_2. 1 hit.
[Graphical view]

Sequences (5)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 5 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P39905-1) [UniParc]FASTAAdd to basket
Also known as: Ex1_4L

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.

« Hide

        10         20         30         40         50
MKLWDVVAVC LVLLHTASAF PLPAGKRPPE APAEDRSLGR RRAPFALSSD
60 70 80 90 100
SNMPEDYPDQ FDDVMDFIQA TIKRLKRSPD KQMAVLPRRE RNRQAAAANP
110 120 130 140 150
ENSRGKGRRG QRGKNRGCVL TAIHLNVTDL GLGYETKEEL IFRYCSGSCD
160 170 180 190 200
AAETTYDKIL KNLSRNRRLV SDKVGQACCR PIAFDDDLSF LDDNLVYHIL
210
RKHSAKRCGC I
Length:211
Mass (Da):23,720
Last modified:February 1, 1995 - v1
Checksum:iA0D1EBF77FC82691
GO
Isoform 2 (identifier: P39905-2) [UniParc]FASTAAdd to basket
Also known as: ATF-1, Ex1_4S, Ex3_4S, HFK2-GDNF

The sequence of this isoform differs from the canonical sequence as follows:
     25-51: GKRPPEAPAEDRSLGRRRAPFALSSDS → A

Show »
Length:185
Mass (Da):20,885
Checksum:i1988C50DA5EA1B10
GO
Isoform 3 (identifier: P39905-3) [UniParc]FASTAAdd to basket
Also known as: Ex2_4L, HFK3-GDNF

The sequence of this isoform differs from the canonical sequence as follows:
     1-1: M → MQSLPNSNGAAAGRDFKM

Show »
Length:228
Mass (Da):25,466
Checksum:i5BAAAC69FEDDBA4C
GO
Isoform 4 (identifier: P39905-4) [UniParc]FASTAAdd to basket
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

Show »
Length:202
Mass (Da):22,631
Checksum:i2CAFBC675D40CF2F
GO
Isoform 5 (identifier: P39905-5) [UniParc]FASTAAdd to basket
Also known as: Ex4S_5

The sequence of this isoform differs from the canonical sequence as follows:
     1-52: Missing.

Note: No experimental confirmation available.
Show »
Length:159
Mass (Da):18,123
Checksum:i97CFDCE97459E34B
GO

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti21 – 211P → S in HSCR3; unknown pathological significance. 1 Publication
Corresponds to variant rs777451569 [ dbSNP | Ensembl ].
VAR_009494
Natural varianti93 – 931R → W in HSCR3 and CCHS; associated to a RET mutation; unknown pathological significance. 2 Publications
Corresponds to variant rs36119840 [ dbSNP | Ensembl ].
VAR_009495
Natural varianti150 – 1501D → N in HSCR3; unknown pathological significance. 1 Publication
Corresponds to variant rs76466003 [ dbSNP | Ensembl ].
VAR_009496
Natural varianti154 – 1541T → S in HSCR3; sporadic form. 1 Publication
Corresponds to variant rs104893891 [ dbSNP | Ensembl ].
VAR_009497
Natural varianti211 – 2111I → M in HSCR3. 1 Publication
Corresponds to variant rs121918536 [ dbSNP | Ensembl ].
VAR_018152

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 5252Missing in isoform 5. CuratedVSP_042298Add
BLAST
Alternative sequencei1 – 11M → MQSLPNSNGAAAGRDFKM in isoform 3 and isoform 4. 1 PublicationVSP_026368
Alternative sequencei25 – 5127GKRPP…LSSDS → A in isoform 2 and isoform 4. 3 PublicationsVSP_006420Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS3922.1. [P39905-1]
CCDS3923.1. [P39905-2]
CCDS54845.1. [P39905-3]
CCDS54846.1. [P39905-4]
CCDS75237.1. [P39905-5]
PIRiB37499.
RefSeqiNP_000505.1. NM_000514.3. [P39905-1]
NP_001177397.1. NM_001190468.1. [P39905-3]
NP_001177398.1. NM_001190469.1. [P39905-4]
NP_001265027.1. NM_001278098.1. [P39905-5]
NP_954701.1. NM_199231.2. [P39905-2]
XP_011512332.1. XM_011514030.2. [P39905-5]
UniGeneiHs.248114.

Genome annotation databases

EnsembliENST00000326524; ENSP00000317145; ENSG00000168621. [P39905-1]
ENST00000344622; ENSP00000339703; ENSG00000168621. [P39905-2]
ENST00000381826; ENSP00000371248; ENSG00000168621. [P39905-4]
ENST00000427982; ENSP00000409007; ENSG00000168621. [P39905-3]
ENST00000515058; ENSP00000425928; ENSG00000168621. [P39905-2]
ENST00000620847; ENSP00000478722; ENSG00000168621. [P39905-5]
GeneIDi2668.
KEGGihsa:2668.
UCSCiuc011cpd.2. human. [P39905-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS3922.1. [P39905-1]
CCDS3923.1. [P39905-2]
CCDS54845.1. [P39905-3]
CCDS54846.1. [P39905-4]
CCDS75237.1. [P39905-5]
PIRiB37499.
RefSeqiNP_000505.1. NM_000514.3. [P39905-1]
NP_001177397.1. NM_001190468.1. [P39905-3]
NP_001177398.1. NM_001190469.1. [P39905-4]
NP_001265027.1. NM_001278098.1. [P39905-5]
NP_954701.1. NM_199231.2. [P39905-2]
XP_011512332.1. XM_011514030.2. [P39905-5]
UniGeneiHs.248114.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
2V5EX-ray2.35B111-211[»]
3FUBX-ray2.35B/D78-211[»]
4UX8electron microscopy24.00D/F78-211[»]
ProteinModelPortaliP39905.
SMRiP39905. Positions 109-211.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi108936. 13 interactions.
DIPiDIP-59051N.
IntActiP39905. 2 interactions.
STRINGi9606.ENSP00000409007.

PTM databases

iPTMnetiP39905.
PhosphoSiteiP39905.

Polymorphism and mutation databases

BioMutaiGDNF.
DMDMi729567.

Proteomic databases

PaxDbiP39905.
PRIDEiP39905.

Protocols and materials databases

DNASUi2668.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000326524; ENSP00000317145; ENSG00000168621. [P39905-1]
ENST00000344622; ENSP00000339703; ENSG00000168621. [P39905-2]
ENST00000381826; ENSP00000371248; ENSG00000168621. [P39905-4]
ENST00000427982; ENSP00000409007; ENSG00000168621. [P39905-3]
ENST00000515058; ENSP00000425928; ENSG00000168621. [P39905-2]
ENST00000620847; ENSP00000478722; ENSG00000168621. [P39905-5]
GeneIDi2668.
KEGGihsa:2668.
UCSCiuc011cpd.2. human. [P39905-1]

Organism-specific databases

CTDi2668.
GeneCardsiGDNF.
GeneReviewsiGDNF.
HGNCiHGNC:4232. GDNF.
HPAiCAB005210.
MalaCardsiGDNF.
MIMi209880. phenotype.
600837. gene.
613711. phenotype.
neXtProtiNX_P39905.
Orphaneti388. Hirschsprung disease.
PharmGKBiPA28644.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410IGT5. Eukaryota.
ENOG4111I3D. LUCA.
GeneTreeiENSGT00520000055559.
HOVERGENiHBG106680.
InParanoidiP39905.
KOiK05452.
OMAiAKRCGCV.
OrthoDBiEOG091G0P1K.
PhylomeDBiP39905.
TreeFamiTF332366.

Enzyme and pathway databases

ReactomeiR-HSA-419037. NCAM1 interactions.
R-HSA-5673001. RAF/MAP kinase cascade.
SignaLinkiP39905.
SIGNORiP39905.

Miscellaneous databases

EvolutionaryTraceiP39905.
GeneWikiiGlial_cell_line-derived_neurotrophic_factor.
GenomeRNAii2668.
PROiP39905.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000168621.
ExpressionAtlasiP39905. baseline and differential.
GenevisibleiP39905. HS.

Family and domain databases

Gene3Di2.10.90.10. 1 hit.
InterProiIPR029034. Cystine-knot_cytokine.
IPR016649. GDNF.
IPR001839. TGF-b_C.
[Graphical view]
PfamiPF00019. TGF_beta. 1 hit.
[Graphical view]
PIRSFiPIRSF016238. GDNF. 1 hit.
SMARTiSM00204. TGFB. 1 hit.
[Graphical view]
SUPFAMiSSF57501. SSF57501. 1 hit.
PROSITEiPS51362. TGF_BETA_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiGDNF_HUMAN
AccessioniPrimary (citable) accession number: P39905
Secondary accession number(s): B7WPK7
, O95448, O95449, O95986, Q6FH33, Q96L44, Q9UD32, Q9UD33, Q9UMV2, Q9UP67, Q9UP97
Entry historyi
Integrated into UniProtKB/Swiss-Prot: February 1, 1995
Last sequence update: February 1, 1995
Last modified: September 7, 2016
This is version 172 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 5
    Human chromosome 5: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.