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Protein

Transient receptor potential cation channel subfamily V member 4

Gene

TRPV4

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

Functioni

Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity. Activation by exposure to hypotonicity within the physiological range exhibits an outward rectification (PubMed:18826956, PubMed:18695040). Also activated by heat, low pH, citrate and phorbol esters (PubMed:18826956, PubMed:18695040). Increase of intracellular Ca2+ potentiates currents. Channel activity seems to be regulated by a calmodulin-dependent mechanism with a negative feedback mechanism (PubMed:12724311, PubMed:18826956). Promotes cell-cell junction formation in skin keratinocytes and plays an important role in the formation and/or maintenance of functional intercellular barriers (By similarity). Acts as a regulator of intracellular Ca2+ in synoviocytes (PubMed:19759329). Plays an obligatory role as a molecular component in the nonselective cation channel activation induced by 4-alpha-phorbol 12,13-didecanoate and hypotonic stimulation in synoviocytes and also regulates production of IL-8 (PubMed:19759329). Together with PKD2, forms mechano- and thermosensitive channels in cilium (PubMed:18695040). Negatively regulates expression of PPARGC1A, UCP1, oxidative metabolism and respiration in adipocytes (By similarity). Regulates expression of chemokines and cytokines related to proinflammatory pathway in adipocytes (By similarity). Together with AQP5, controls regulatory volume decrease in salivary epithelial cells (By similarity).By similarity5 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei192ATP1 Publication1
Binding sitei201ATP1 Publication1
Binding sitei239ATP1 Publication1
Binding sitei248ATP1 Publication1

GO - Molecular functioni

  • actin binding Source: BHF-UCL
  • actin filament binding Source: BHF-UCL
  • alpha-tubulin binding Source: BHF-UCL
  • ATP binding Source: UniProtKB-KW
  • beta-tubulin binding Source: BHF-UCL
  • calcium channel activity Source: UniProtKB
  • calmodulin binding Source: UniProtKB
  • cation channel activity Source: UniProtKB
  • microtubule binding Source: BHF-UCL
  • osmosensor activity Source: Ensembl
  • protein kinase binding Source: BHF-UCL
  • protein kinase C binding Source: BHF-UCL
  • SH2 domain binding Source: BHF-UCL
  • stretch-activated, cation-selective, calcium channel activity Source: UniProtKB

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Calcium channel, Ion channel

Keywords - Biological processi

Calcium transport, Ion transport, Transport

Keywords - Ligandi

ATP-binding, Calcium, Calmodulin-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiR-HSA-3295583. TRP channels.
SignaLinkiQ9HBA0.

Names & Taxonomyi

Protein namesi
Recommended name:
Transient receptor potential cation channel subfamily V member 4
Short name:
TrpV4
Alternative name(s):
Osm-9-like TRP channel 4
Short name:
OTRPC4
Transient receptor potential protein 12
Short name:
TRP12
Vanilloid receptor-like channel 2
Vanilloid receptor-like protein 2
Short name:
VRL-2
Vanilloid receptor-related osmotically-activated channel
Short name:
VR-OAC
Gene namesi
Name:TRPV4
Synonyms:VRL2, VROAC
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 12

Organism-specific databases

HGNCiHGNC:18083. TRPV4.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 465CytoplasmicSequence analysisAdd BLAST465
Transmembranei466 – 486HelicalSequence analysisAdd BLAST21
Topological domaini487 – 508ExtracellularSequence analysisAdd BLAST22
Transmembranei509 – 529HelicalSequence analysisAdd BLAST21
Topological domaini530 – 550CytoplasmicSequence analysisAdd BLAST21
Transmembranei551 – 571HelicalSequence analysisAdd BLAST21
Topological domaini572ExtracellularSequence analysis1
Transmembranei573 – 593HelicalSequence analysisAdd BLAST21
Topological domaini594 – 616CytoplasmicSequence analysisAdd BLAST23
Transmembranei617 – 637HelicalSequence analysisAdd BLAST21
Intramembranei648 – 678Pore-formingCuratedAdd BLAST31
Transmembranei691 – 711HelicalSequence analysisAdd BLAST21
Topological domaini712 – 871CytoplasmicSequence analysisAdd BLAST160

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cell junction, Cell membrane, Cell projection, Cilium, Membrane

Pathology & Biotechi

Involvement in diseasei

Brachyolmia 3 (BCYM3)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA form of brachyolmia, a clinically and genetically heterogeneous skeletal dysplasia primarily affecting the spine and characterized by a short trunk, short stature, and platyspondyly. BCYM3 is an autosomal dominant form with severe scoliosis with or without kyphosis, and flattened irregular cervical vertebrae.
See also OMIM:113500
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_054805616R → Q in BCYM3; this mutation results in a gain of function and a constitutive activation of the channel. 1 PublicationCorresponds to variant rs121912632dbSNPEnsembl.1
Natural variantiVAR_054806620V → I in BCYM3; this mutation results in a gain of function and a constitutive activation of the channel. 1 PublicationCorresponds to variant rs121912633dbSNPEnsembl.1
Spondylometaphyseal dysplasia Kozlowski type (SMDK)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA form of spondylometaphyseal dysplasia, a group of short stature disorders distinguished by abnormalities in the vertebrae and the metaphyses of the tubular bones. It is characterized by postnatal dwarfism, significant scoliosis and mild metaphyseal abnormalities in the pelvis. The vertebrae exhibit platyspondyly and overfaced pedicles.
See also OMIM:184252
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_064521278E → K in SMDK. 1 PublicationCorresponds to variant rs267607148dbSNPEnsembl.1
Natural variantiVAR_067992333 – 336Missing in SMDK. 4
Natural variantiVAR_062332333D → G in SMDK. 1 PublicationCorresponds to variant rs121912634dbSNPEnsembl.1
Natural variantiVAR_062333594R → H in SMDK and PSTD. 3 PublicationsCorresponds to variant rs77975504dbSNPEnsembl.1
Natural variantiVAR_064527596L → P in SMDK. 1 PublicationCorresponds to variant rs515726159dbSNPEnsembl.1
Natural variantiVAR_064528600G → W in SMDK. 1 PublicationCorresponds to variant rs515726160dbSNPEnsembl.1
Natural variantiVAR_064533625M → I in SMDK. 1 PublicationCorresponds to variant rs515726164dbSNPEnsembl.1
Natural variantiVAR_064534709L → M in SMDK. 1 PublicationCorresponds to variant rs116571438dbSNPEnsembl.1
Natural variantiVAR_062334716A → S in SMDK. 1 PublicationCorresponds to variant rs121912635dbSNPEnsembl.1
Natural variantiVAR_064536777C → Y in SMDK. 1 PublicationCorresponds to variant rs515726165dbSNPEnsembl.1
Natural variantiVAR_064537797E → K in MTD and SMDK; also found in a patient with spondyloepiphyseal dysplasia Maroteaux type. 3 PublicationsCorresponds to variant rs267607149dbSNPEnsembl.1
Metatropic dysplasia (MTD)4 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA severe spondyloepimetaphyseal dysplasia characterized by short limbs with limitation and enlargement of joints and usually severe kyphoscoliosis. Radiologic features include severe platyspondyly, severe metaphyseal enlargement and shortening of long bones.
See also OMIM:156530
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06451789T → I in MTD; lethal form. 1 PublicationCorresponds to variant rs397514473dbSNPEnsembl.1
Natural variantiVAR_064519197K → R in MTD; lethal form. 1 PublicationCorresponds to variant rs387906903dbSNPEnsembl.1
Natural variantiVAR_064520199L → F in MTD. 1 PublicationCorresponds to variant rs515726167dbSNPEnsembl.1
Natural variantiVAR_064522295T → A in MTD. 1 PublicationCorresponds to variant rs515726171dbSNPEnsembl.1
Natural variantiVAR_062331331I → F in MTD. 2 PublicationsCorresponds to variant rs121912636dbSNPEnsembl.1
Natural variantiVAR_064523331I → T in MTD. 1 PublicationCorresponds to variant rs515726172dbSNPEnsembl.1
Natural variantiVAR_064524342V → F in MTD. 1 PublicationCorresponds to variant rs515726152dbSNPEnsembl.1
Natural variantiVAR_064525471Missing in MTD; lethal form. 2 Publications1
Natural variantiVAR_064526592F → L in MTD. 1 PublicationCorresponds to variant rs515726158dbSNPEnsembl.1
Natural variantiVAR_064530604I → M in MTD; lethal form. 1 PublicationCorresponds to variant rs515726161dbSNPEnsembl.1
Natural variantiVAR_064531617F → L in MTD. 1 PublicationCorresponds to variant rs515726162dbSNPEnsembl.1
Natural variantiVAR_064532618L → P in MTD. 2 PublicationsCorresponds to variant rs515726163dbSNPEnsembl.1
Natural variantiVAR_064535775R → K in MTD. 1 Publication1
Natural variantiVAR_064537797E → K in MTD and SMDK; also found in a patient with spondyloepiphyseal dysplasia Maroteaux type. 3 PublicationsCorresponds to variant rs267607149dbSNPEnsembl.1
Natural variantiVAR_064538799P → A in MTD. 1 PublicationCorresponds to variant rs267607147dbSNPEnsembl.1
Natural variantiVAR_062335799P → L in MTD; also found in a patient with spondyloepiphyseal dysplasia Maroteaux type. 4 PublicationsCorresponds to variant rs121912637dbSNPEnsembl.1
Natural variantiVAR_064539799P → R in MTD. 1 PublicationCorresponds to variant rs121912637dbSNPEnsembl.1
Natural variantiVAR_064540799P → S in MTD. 1 PublicationCorresponds to variant rs267607147dbSNPEnsembl.1
Neuronopathy, distal hereditary motor, 8 (HMN8)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA clinically variable, neuromuscular disorder characterized by congenital lower motor neuron disorder restricted to the lower part of the body. Clinical manifestations include non-progressive muscular atrophy, thigh muscle atrophy, weak thigh adductors, weak knee and foot extensors, minimal jaw muscle and neck flexor weakness, flexion contractures of knees and pes equinovarus. Tendon reflexes are normal.
See also OMIM:600175
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06798997P → R in HMN8; loss of function mutation. 1 Publication1
Natural variantiVAR_067990232R → C in HMN8 and CMT2C; does not affect channel localization to plasma membrane; results in increased agonist-induced channel activity and increased basal intracellular calcium concentration; causes increased cell death. 2 PublicationsCorresponds to variant rs387906904dbSNPEnsembl.1
Natural variantiVAR_063529269R → H in HMN8 and CMT2C; increased agonist-induced channel activity and increased basal intracellular calcium concentration; causes increased cell death. 4 PublicationsCorresponds to variant rs267607144dbSNPEnsembl.1
Charcot-Marie-Tooth disease 2C (CMT2C)5 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAn axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. Nerve conduction velocities are normal or slightly reduced.
See also OMIM:606071
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_067990232R → C in HMN8 and CMT2C; does not affect channel localization to plasma membrane; results in increased agonist-induced channel activity and increased basal intracellular calcium concentration; causes increased cell death. 2 PublicationsCorresponds to variant rs387906904dbSNPEnsembl.1
Natural variantiVAR_063528269R → C in CMT2C. 2 PublicationsCorresponds to variant rs267607146dbSNPEnsembl.1
Natural variantiVAR_063529269R → H in HMN8 and CMT2C; increased agonist-induced channel activity and increased basal intracellular calcium concentration; causes increased cell death. 4 PublicationsCorresponds to variant rs267607144dbSNPEnsembl.1
Natural variantiVAR_063541315R → W in CMT2C. 2 PublicationsCorresponds to variant rs267607143dbSNPEnsembl.1
Natural variantiVAR_063530316R → C in CMT2C and SPSMA. 2 PublicationsCorresponds to variant rs267607145dbSNPEnsembl.1
Natural variantiVAR_067991316R → H in CMT2C; does not affect channel localization to plasma membrane; results in increased agonist-induced channel activity and increased basal intracellular calcium concentration; causes increased cell death. 1 PublicationCorresponds to variant rs387906905dbSNPEnsembl.1
Natural variantiVAR_067993542S → Y in CMT2C. 1 PublicationCorresponds to variant rs387906902dbSNPEnsembl.1
Scapuloperoneal spinal muscular atrophy (SPSMA)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA clinically variable neuromuscular disorder characterized by neurogenic scapuloperoneal amyotrophy, laryngeal palsy, congenital absence of muscles, progressive scapuloperoneal atrophy and progressive distal weakness and amyotrophy.
See also OMIM:181405
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_063530316R → C in CMT2C and SPSMA. 2 PublicationsCorresponds to variant rs267607145dbSNPEnsembl.1
Spondyloepiphyseal dysplasia Maroteaux type (SEDM)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA clinically variable spondyloepiphyseal dysplasia with manifestations limited to the musculoskeletal system. Clinical features include short stature, brachydactyly, platyspondyly, short and stubby hands and feet, epiphyseal hypoplasia of the large joints, and iliac hypoplasia. Intelligence is normal.
See also OMIM:184095
Parastremmatic dwarfism (PSTD)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA bone dysplasia characterized by severe dwarfism, kyphoscoliosis, distortion and bowing of the extremities, and contractures of the large joints. Radiographically, the disease is characterized by a combination of decreased bone density, bowing of the long bones, platyspondyly and striking irregularities of endochondral ossification with areas of calcific stippling and streaking in radiolucent epiphyses, metaphyses and apophyses.
See also OMIM:168400
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_062333594R → H in SMDK and PSTD. 3 PublicationsCorresponds to variant rs77975504dbSNPEnsembl.1
Digital arthropathy-brachydactyly, familial (FDAB)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA disorder characterized by irregularities in the proximal articular surfaces of the distal interphalangeal joints of the hand. Individuals appear normal at birth, with no clinical or radiographic evidence of a developmental skeletal dysplasia. The earliest changes appear during the first decade of life. By adulthood, all interphalangeal, metacarpophalangeal, and metatarsophalangeal joints are affected by a deforming, painful osteoarthritis. The remainder of the skeleton is clinically and radiographically unaffected.
See also OMIM:606835
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_068498270G → V in FDAB; poorly expressed on the cell surface; mutant channels show a significantly reduced response to agonists. 1 PublicationCorresponds to variant rs387907220dbSNPEnsembl.1
Natural variantiVAR_068499271R → P in FDAB; poorly expressed on the cell surface; mutant channels show a significantly reduced response to agonists. 1 PublicationCorresponds to variant rs387907219dbSNPEnsembl.1
Natural variantiVAR_068500273F → L in FDAB; poorly expressed on the cell surface; mutant channels show a significantly reduced response to agonists. 1 PublicationCorresponds to variant rs515726170dbSNPEnsembl.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi816 – 821RLRRDR → ELEEDE: Loss of calmodulin binding; when associated with A-828. 6
Mutagenesisi821 – 824RWSS → AASA: Loss of calmodulin binding. 4
Mutagenesisi822W → A: Loss of Ca(2+) dependent current potentiation. 1
Mutagenesisi828R → A: Loss of calmodulin binding; when associated with 816-ELEEDE-821. 1 Publication1

Keywords - Diseasei

Charcot-Marie-Tooth disease, Disease mutation, Dwarfism, Neurodegeneration, Neuropathy

Organism-specific databases

DisGeNETi59341.
MalaCardsiTRPV4.
MIMi113500. phenotype.
156530. phenotype.
168400. phenotype.
181405. phenotype.
184095. phenotype.
184252. phenotype.
600175. phenotype.
606071. phenotype.
606835. phenotype.
613508. phenotype.
OpenTargetsiENSG00000111199.
Orphaneti93304. Autosomal dominant brachyolmia.
99937. Autosomal dominant Charcot-Marie-Tooth disease type 2C.
1216. Autosomal dominant congenital benign spinal muscular atrophy.
85169. Familial digital arthropathy-brachydactyly.
2635. Metatropic dysplasia.
2646. Parastremmatic dwarfism.
263482. Spondyloepiphyseal dysplasia, Maroteaux type.
93314. Spondylometaphyseal dysplasia, Kozlowski type.
PharmGKBiPA38293.

Chemistry databases

ChEMBLiCHEMBL3119.
GuidetoPHARMACOLOGYi510.

Polymorphism and mutation databases

BioMutaiTRPV4.
DMDMi62901470.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002153471 – 871Transient receptor potential cation channel subfamily V member 4Add BLAST871

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei110PhosphotyrosineBy similarity1
Modified residuei805PhosphotyrosineBy similarity1
Modified residuei824PhosphoserineBy similarity1

Keywords - PTMi

Phosphoprotein

Proteomic databases

MaxQBiQ9HBA0.
PaxDbiQ9HBA0.
PeptideAtlasiQ9HBA0.
PRIDEiQ9HBA0.

PTM databases

iPTMnetiQ9HBA0.
PhosphoSitePlusiQ9HBA0.

Expressioni

Tissue specificityi

Found in the synoviocytes from patients with (RA) and without (CTR) rheumatoid arthritis (at protein level).1 Publication

Gene expression databases

BgeeiENSG00000111199.
ExpressionAtlasiQ9HBA0. baseline and differential.
GenevisibleiQ9HBA0. HS.

Organism-specific databases

HPAiHPA007150.

Interactioni

Subunit structurei

Homotetramer (Probable). Self-associates in a isoform-specific manner (PubMed:16293632). Isoforms 1/A and 5/D but not isoform 2/B, 4/C and 6/E can oligomerize (PubMed:16293632). Interacts with calmodulin (PubMed:12724311). Interacts with Map7 and Src family Tyr protein kinases LYN, SRC, FYN, HCK, LCK and YES (By similarity). Interacts with CTNNB1 (By similarity). The TRPV4 and CTNNB1 complex can interact with CDH1 (By similarity). Interacts with PACSIN1, PACSIN2 and PACSIN3 (via SH3 domain) (By similarity). Part of a complex containing MLC1, AQP4, HEPACAM and ATP1B1 (PubMed:22328087). Interacts with ITPR3 (PubMed:18826956). Interacts with AQP5; the interaction is probably indirect and regulates TRPV4 activation by hypotonicity (By similarity). Interacts with ANO1 (By similarity). Interacts (via C-terminus) with PKD2 (via C-terminus) (PubMed:18695040).By similarityCurated6 Publications

GO - Molecular functioni

  • actin binding Source: BHF-UCL
  • actin filament binding Source: BHF-UCL
  • alpha-tubulin binding Source: BHF-UCL
  • beta-tubulin binding Source: BHF-UCL
  • calmodulin binding Source: UniProtKB
  • microtubule binding Source: BHF-UCL
  • protein kinase binding Source: BHF-UCL
  • protein kinase C binding Source: BHF-UCL
  • SH2 domain binding Source: BHF-UCL

Protein-protein interaction databases

BioGridi121883. 11 interactors.
DIPiDIP-35702N.
IntActiQ9HBA0. 6 interactors.
MINTiMINT-4535111.
STRINGi9606.ENSP00000261740.

Chemistry databases

BindingDBiQ9HBA0.

Structurei

Secondary structure

1871
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi151 – 159Combined sources9
Helixi164 – 166Combined sources3
Helixi169 – 175Combined sources7
Helixi183 – 185Combined sources3
Beta strandi188 – 190Combined sources3
Helixi194 – 200Combined sources7
Helixi209 – 220Combined sources12
Helixi223 – 228Combined sources6
Beta strandi234 – 239Combined sources6
Helixi241 – 247Combined sources7
Helixi251 – 260Combined sources10
Helixi271 – 273Combined sources3
Turni276 – 279Combined sources4
Helixi288 – 294Combined sources7
Helixi298 – 306Combined sources9
Helixi324 – 331Combined sources8
Helixi336 – 356Combined sources21
Beta strandi357 – 360Combined sources4
Helixi362 – 364Combined sources3
Helixi373 – 379Combined sources7
Helixi383 – 395Combined sources13

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4DX1X-ray2.85A/B149-397[»]
4DX2X-ray2.95A/B149-397[»]
ProteinModelPortaliQ9HBA0.
SMRiQ9HBA0.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Repeati237 – 266ANK 1Add BLAST30
Repeati284 – 313ANK 2Add BLAST30
Repeati369 – 398ANK 3Add BLAST30

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni812 – 831Interaction with calmodulin and ITPR32 PublicationsAdd BLAST20

Sequence similaritiesi

Contains 3 ANK repeats.PROSITE-ProRule annotation

Keywords - Domaini

ANK repeat, Repeat, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG3676. Eukaryota.
ENOG4110DG4. LUCA.
GeneTreeiENSGT00550000074425.
HOVERGENiHBG054085.
InParanoidiQ9HBA0.
KOiK04973.
OMAiKSETYQY.
OrthoDBiEOG091G016O.
PhylomeDBiQ9HBA0.
TreeFamiTF314711.

Family and domain databases

Gene3Di1.25.40.20. 1 hit.
InterProiIPR002110. Ankyrin_rpt.
IPR020683. Ankyrin_rpt-contain_dom.
IPR005821. Ion_trans_dom.
IPR004729. TRP_channel.
IPR008347. TRPV1-4_channel.
IPR008348. TRPV4_channel.
[Graphical view]
PANTHERiPTHR10582:SF4. PTHR10582:SF4. 2 hits.
PfamiPF00023. Ank. 1 hit.
PF00520. Ion_trans. 1 hit.
[Graphical view]
PRINTSiPR01768. TRPVRECEPTOR.
PR01769. VRL2RECEPTOR.
SMARTiSM00248. ANK. 3 hits.
[Graphical view]
SUPFAMiSSF48403. SSF48403. 1 hit.
TIGRFAMsiTIGR00870. trp. 1 hit.
PROSITEiPS50297. ANK_REP_REGION. 1 hit.
PS50088. ANK_REPEAT. 1 hit.
[Graphical view]

Sequences (6)i

Sequence statusi: Complete.

This entry describes 6 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9HBA0-1) [UniParc]FASTAAdd to basket
Also known as: A

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
MADSSEGPRA GPGEVAELPG DESGTPGGEA FPLSSLANLF EGEDGSLSPS
60 70 80 90 100
PADASRPAGP GDGRPNLRMK FQGAFRKGVP NPIDLLESTL YESSVVPGPK
110 120 130 140 150
KAPMDSLFDY GTYRHHSSDN KRWRKKIIEK QPQSPKAPAP QPPPILKVFN
160 170 180 190 200
RPILFDIVSR GSTADLDGLL PFLLTHKKRL TDEEFREPST GKTCLPKALL
210 220 230 240 250
NLSNGRNDTI PVLLDIAERT GNMREFINSP FRDIYYRGQT ALHIAIERRC
260 270 280 290 300
KHYVELLVAQ GADVHAQARG RFFQPKDEGG YFYFGELPLS LAACTNQPHI
310 320 330 340 350
VNYLTENPHK KADMRRQDSR GNTVLHALVA IADNTRENTK FVTKMYDLLL
360 370 380 390 400
LKCARLFPDS NLEAVLNNDG LSPLMMAAKT GKIGIFQHII RREVTDEDTR
410 420 430 440 450
HLSRKFKDWA YGPVYSSLYD LSSLDTCGEE ASVLEILVYN SKIENRHEML
460 470 480 490 500
AVEPINELLR DKWRKFGAVS FYINVVSYLC AMVIFTLTAY YQPLEGTPPY
510 520 530 540 550
PYRTTVDYLR LAGEVITLFT GVLFFFTNIK DLFMKKCPGV NSLFIDGSFQ
560 570 580 590 600
LLYFIYSVLV IVSAALYLAG IEAYLAVMVF ALVLGWMNAL YFTRGLKLTG
610 620 630 640 650
TYSIMIQKIL FKDLFRFLLV YLLFMIGYAS ALVSLLNPCA NMKVCNEDQT
660 670 680 690 700
NCTVPTYPSC RDSETFSTFL LDLFKLTIGM GDLEMLSSTK YPVVFIILLV
710 720 730 740 750
TYIILTFVLL LNMLIALMGE TVGQVSKESK HIWKLQWATT ILDIERSFPV
760 770 780 790 800
FLRKAFRSGE MVTVGKSSDG TPDRRWCFRV DEVNWSHWNQ NLGIINEDPG
810 820 830 840 850
KNETYQYYGF SHTVGRLRRD RWSSVVPRVV ELNKNSNPDE VVVPLDSMGN
860 870
PRCDGHQQGY PRKWRTDDAP L
Length:871
Mass (Da):98,281
Last modified:April 26, 2005 - v2
Checksum:iC62056B86C5A6FB6
GO
Isoform 2 (identifier: Q9HBA0-2) [UniParc]FASTAAdd to basket
Also known as: B, OTRPC4beta

The sequence of this isoform differs from the canonical sequence as follows:
     385-444: Missing.

Show »
Length:811
Mass (Da):91,261
Checksum:iA498FF4BBA1CD7A5
GO
Isoform 3 (identifier: Q9HBA0-3) [UniParc]FASTAAdd to basket
Also known as: TRPV-SV

The sequence of this isoform differs from the canonical sequence as follows:
     844-871: PLDSMGNPRCDGHQQGYPRKWRTDDAPL → RHLCRVRRKR

Show »
Length:853
Mass (Da):96,449
Checksum:iEAA07196606AED20
GO
Isoform 4 (identifier: Q9HBA0-4) [UniParc]FASTAAdd to basket
Also known as: C

The sequence of this isoform differs from the canonical sequence as follows:
     239-285: Missing.

Show »
Length:824
Mass (Da):92,904
Checksum:iEA7AFC7497D14495
GO
Isoform 5 (identifier: Q9HBA0-5) [UniParc]FASTAAdd to basket
Also known as: D

The sequence of this isoform differs from the canonical sequence as follows:
     28-61: Missing.

Show »
Length:837
Mass (Da):94,998
Checksum:i1538A7B2E76C8CDF
GO
Isoform 6 (identifier: Q9HBA0-6) [UniParc]FASTAAdd to basket
Also known as: E

The sequence of this isoform differs from the canonical sequence as follows:
     239-285: Missing.
     385-444: Missing.

Show »
Length:764
Mass (Da):85,884
Checksum:iB1307888F82B0E31
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti385I → V in AAG28029 (PubMed:11081638).Curated1
Sequence conflicti452V → A in BAC06573 (Ref. 6) Curated1
Sequence conflicti781D → N in AAG28029 (PubMed:11081638).Curated1
Sequence conflicti820D → T in BAB69040 (Ref. 4) Curated1
Sequence conflicti861P → T in BAC06573 (Ref. 6) Curated1
Sequence conflicti867D → E in AAG16127 (PubMed:11025659).Curated1

Polymorphismi

Genetic variations in TRPV4 determine the sodium serum level quantitative trait locus 1 (SSQTL1) [MIMi:613508]. In some populations, variant Pro19Ser has been shown to be significantly associated with hyponatremia defined as serum sodium concentration below or equal to 135 mEq/L.

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_05239119P → S Associated with lower sodium concentraions in serum; shows diminished response to hypotonic stress relative to wild-type. Corresponds to variant rs3742030dbSNPEnsembl.1
Natural variantiVAR_06451789T → I in MTD; lethal form. 1 PublicationCorresponds to variant rs397514473dbSNPEnsembl.1
Natural variantiVAR_06798997P → R in HMN8; loss of function mutation. 1 Publication1
Natural variantiVAR_064518183E → K Found in a patient with spondyloepiphyseal dysplasia Maroteaux type. 1 PublicationCorresponds to variant rs387906324dbSNPEnsembl.1
Natural variantiVAR_064519197K → R in MTD; lethal form. 1 PublicationCorresponds to variant rs387906903dbSNPEnsembl.1
Natural variantiVAR_064520199L → F in MTD. 1 PublicationCorresponds to variant rs515726167dbSNPEnsembl.1
Natural variantiVAR_067990232R → C in HMN8 and CMT2C; does not affect channel localization to plasma membrane; results in increased agonist-induced channel activity and increased basal intracellular calcium concentration; causes increased cell death. 2 PublicationsCorresponds to variant rs387906904dbSNPEnsembl.1
Natural variantiVAR_063528269R → C in CMT2C. 2 PublicationsCorresponds to variant rs267607146dbSNPEnsembl.1
Natural variantiVAR_063529269R → H in HMN8 and CMT2C; increased agonist-induced channel activity and increased basal intracellular calcium concentration; causes increased cell death. 4 PublicationsCorresponds to variant rs267607144dbSNPEnsembl.1
Natural variantiVAR_068498270G → V in FDAB; poorly expressed on the cell surface; mutant channels show a significantly reduced response to agonists. 1 PublicationCorresponds to variant rs387907220dbSNPEnsembl.1
Natural variantiVAR_068499271R → P in FDAB; poorly expressed on the cell surface; mutant channels show a significantly reduced response to agonists. 1 PublicationCorresponds to variant rs387907219dbSNPEnsembl.1
Natural variantiVAR_068500273F → L in FDAB; poorly expressed on the cell surface; mutant channels show a significantly reduced response to agonists. 1 PublicationCorresponds to variant rs515726170dbSNPEnsembl.1
Natural variantiVAR_064521278E → K in SMDK. 1 PublicationCorresponds to variant rs267607148dbSNPEnsembl.1
Natural variantiVAR_064522295T → A in MTD. 1 PublicationCorresponds to variant rs515726171dbSNPEnsembl.1
Natural variantiVAR_063541315R → W in CMT2C. 2 PublicationsCorresponds to variant rs267607143dbSNPEnsembl.1
Natural variantiVAR_063530316R → C in CMT2C and SPSMA. 2 PublicationsCorresponds to variant rs267607145dbSNPEnsembl.1
Natural variantiVAR_067991316R → H in CMT2C; does not affect channel localization to plasma membrane; results in increased agonist-induced channel activity and increased basal intracellular calcium concentration; causes increased cell death. 1 PublicationCorresponds to variant rs387906905dbSNPEnsembl.1
Natural variantiVAR_062331331I → F in MTD. 2 PublicationsCorresponds to variant rs121912636dbSNPEnsembl.1
Natural variantiVAR_064523331I → T in MTD. 1 PublicationCorresponds to variant rs515726172dbSNPEnsembl.1
Natural variantiVAR_067992333 – 336Missing in SMDK. 4
Natural variantiVAR_062332333D → G in SMDK. 1 PublicationCorresponds to variant rs121912634dbSNPEnsembl.1
Natural variantiVAR_064524342V → F in MTD. 1 PublicationCorresponds to variant rs515726152dbSNPEnsembl.1
Natural variantiVAR_064525471Missing in MTD; lethal form. 2 Publications1
Natural variantiVAR_067993542S → Y in CMT2C. 1 PublicationCorresponds to variant rs387906902dbSNPEnsembl.1
Natural variantiVAR_064526592F → L in MTD. 1 PublicationCorresponds to variant rs515726158dbSNPEnsembl.1
Natural variantiVAR_062333594R → H in SMDK and PSTD. 3 PublicationsCorresponds to variant rs77975504dbSNPEnsembl.1
Natural variantiVAR_064527596L → P in SMDK. 1 PublicationCorresponds to variant rs515726159dbSNPEnsembl.1
Natural variantiVAR_064528600G → W in SMDK. 1 PublicationCorresponds to variant rs515726160dbSNPEnsembl.1
Natural variantiVAR_064529602Y → C Found in a patient with spondyloepiphyseal dysplasia Maroteaux type. 1 PublicationCorresponds to variant rs267607150dbSNPEnsembl.1
Natural variantiVAR_064530604I → M in MTD; lethal form. 1 PublicationCorresponds to variant rs515726161dbSNPEnsembl.1
Natural variantiVAR_054805616R → Q in BCYM3; this mutation results in a gain of function and a constitutive activation of the channel. 1 PublicationCorresponds to variant rs121912632dbSNPEnsembl.1
Natural variantiVAR_064531617F → L in MTD. 1 PublicationCorresponds to variant rs515726162dbSNPEnsembl.1
Natural variantiVAR_064532618L → P in MTD. 2 PublicationsCorresponds to variant rs515726163dbSNPEnsembl.1
Natural variantiVAR_054806620V → I in BCYM3; this mutation results in a gain of function and a constitutive activation of the channel. 1 PublicationCorresponds to variant rs121912633dbSNPEnsembl.1
Natural variantiVAR_064533625M → I in SMDK. 1 PublicationCorresponds to variant rs515726164dbSNPEnsembl.1
Natural variantiVAR_064534709L → M in SMDK. 1 PublicationCorresponds to variant rs116571438dbSNPEnsembl.1
Natural variantiVAR_062334716A → S in SMDK. 1 PublicationCorresponds to variant rs121912635dbSNPEnsembl.1
Natural variantiVAR_064535775R → K in MTD. 1 Publication1
Natural variantiVAR_064536777C → Y in SMDK. 1 PublicationCorresponds to variant rs515726165dbSNPEnsembl.1
Natural variantiVAR_064537797E → K in MTD and SMDK; also found in a patient with spondyloepiphyseal dysplasia Maroteaux type. 3 PublicationsCorresponds to variant rs267607149dbSNPEnsembl.1
Natural variantiVAR_064538799P → A in MTD. 1 PublicationCorresponds to variant rs267607147dbSNPEnsembl.1
Natural variantiVAR_062335799P → L in MTD; also found in a patient with spondyloepiphyseal dysplasia Maroteaux type. 4 PublicationsCorresponds to variant rs121912637dbSNPEnsembl.1
Natural variantiVAR_064539799P → R in MTD. 1 PublicationCorresponds to variant rs121912637dbSNPEnsembl.1
Natural variantiVAR_064540799P → S in MTD. 1 PublicationCorresponds to variant rs267607147dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_02661428 – 61Missing in isoform 5. 1 PublicationAdd BLAST34
Alternative sequenceiVSP_026615239 – 285Missing in isoform 4 and isoform 6. 1 PublicationAdd BLAST47
Alternative sequenceiVSP_013436385 – 444Missing in isoform 2 and isoform 6. 2 PublicationsAdd BLAST60
Alternative sequenceiVSP_013437844 – 871PLDSM…DDAPL → RHLCRVRRKR in isoform 3. 1 PublicationAdd BLAST28

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF263523 mRNA. Translation: AAG28029.1.
AF258465 mRNA. Translation: AAG16127.1.
AB100308 mRNA. Translation: BAC55864.1.
AB032427 mRNA. Translation: BAB69040.1.
AB073669 mRNA. Translation: BAC06573.1.
AJ296305 mRNA. Translation: CAC82937.1.
DQ059644 mRNA. Translation: AAZ04918.1.
DQ059645 mRNA. Translation: AAZ04919.1.
DQ059646 mRNA. Translation: AAZ04920.1.
CH471054 Genomic DNA. Translation: EAW97879.1.
BC117426 mRNA. Translation: AAI17427.1.
BC143315 mRNA. Translation: AAI43316.1.
AF279673 mRNA. Translation: AAK69487.1.
CCDSiCCDS53827.1. [Q9HBA0-6]
CCDS53828.1. [Q9HBA0-4]
CCDS53829.1. [Q9HBA0-5]
CCDS9134.1. [Q9HBA0-1]
CCDS9135.1. [Q9HBA0-2]
RefSeqiNP_001170899.1. NM_001177428.1. [Q9HBA0-4]
NP_001170902.1. NM_001177431.1. [Q9HBA0-5]
NP_001170904.1. NM_001177433.1. [Q9HBA0-6]
NP_067638.3. NM_021625.4. [Q9HBA0-1]
NP_671737.1. NM_147204.2. [Q9HBA0-2]
XP_005253975.1. XM_005253918.1. [Q9HBA0-1]
XP_016875263.1. XM_017019774.1. [Q9HBA0-1]
UniGeneiHs.506713.

Genome annotation databases

EnsembliENST00000261740; ENSP00000261740; ENSG00000111199. [Q9HBA0-1]
ENST00000418703; ENSP00000406191; ENSG00000111199. [Q9HBA0-1]
ENST00000536838; ENSP00000444336; ENSG00000111199. [Q9HBA0-5]
ENST00000537083; ENSP00000442738; ENSG00000111199. [Q9HBA0-2]
ENST00000541794; ENSP00000442167; ENSG00000111199. [Q9HBA0-4]
ENST00000544971; ENSP00000443611; ENSG00000111199. [Q9HBA0-6]
GeneIDi59341.
KEGGihsa:59341.
UCSCiuc001tpg.3. human. [Q9HBA0-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF263523 mRNA. Translation: AAG28029.1.
AF258465 mRNA. Translation: AAG16127.1.
AB100308 mRNA. Translation: BAC55864.1.
AB032427 mRNA. Translation: BAB69040.1.
AB073669 mRNA. Translation: BAC06573.1.
AJ296305 mRNA. Translation: CAC82937.1.
DQ059644 mRNA. Translation: AAZ04918.1.
DQ059645 mRNA. Translation: AAZ04919.1.
DQ059646 mRNA. Translation: AAZ04920.1.
CH471054 Genomic DNA. Translation: EAW97879.1.
BC117426 mRNA. Translation: AAI17427.1.
BC143315 mRNA. Translation: AAI43316.1.
AF279673 mRNA. Translation: AAK69487.1.
CCDSiCCDS53827.1. [Q9HBA0-6]
CCDS53828.1. [Q9HBA0-4]
CCDS53829.1. [Q9HBA0-5]
CCDS9134.1. [Q9HBA0-1]
CCDS9135.1. [Q9HBA0-2]
RefSeqiNP_001170899.1. NM_001177428.1. [Q9HBA0-4]
NP_001170902.1. NM_001177431.1. [Q9HBA0-5]
NP_001170904.1. NM_001177433.1. [Q9HBA0-6]
NP_067638.3. NM_021625.4. [Q9HBA0-1]
NP_671737.1. NM_147204.2. [Q9HBA0-2]
XP_005253975.1. XM_005253918.1. [Q9HBA0-1]
XP_016875263.1. XM_017019774.1. [Q9HBA0-1]
UniGeneiHs.506713.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4DX1X-ray2.85A/B149-397[»]
4DX2X-ray2.95A/B149-397[»]
ProteinModelPortaliQ9HBA0.
SMRiQ9HBA0.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi121883. 11 interactors.
DIPiDIP-35702N.
IntActiQ9HBA0. 6 interactors.
MINTiMINT-4535111.
STRINGi9606.ENSP00000261740.

Chemistry databases

BindingDBiQ9HBA0.
ChEMBLiCHEMBL3119.
GuidetoPHARMACOLOGYi510.

PTM databases

iPTMnetiQ9HBA0.
PhosphoSitePlusiQ9HBA0.

Polymorphism and mutation databases

BioMutaiTRPV4.
DMDMi62901470.

Proteomic databases

MaxQBiQ9HBA0.
PaxDbiQ9HBA0.
PeptideAtlasiQ9HBA0.
PRIDEiQ9HBA0.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000261740; ENSP00000261740; ENSG00000111199. [Q9HBA0-1]
ENST00000418703; ENSP00000406191; ENSG00000111199. [Q9HBA0-1]
ENST00000536838; ENSP00000444336; ENSG00000111199. [Q9HBA0-5]
ENST00000537083; ENSP00000442738; ENSG00000111199. [Q9HBA0-2]
ENST00000541794; ENSP00000442167; ENSG00000111199. [Q9HBA0-4]
ENST00000544971; ENSP00000443611; ENSG00000111199. [Q9HBA0-6]
GeneIDi59341.
KEGGihsa:59341.
UCSCiuc001tpg.3. human. [Q9HBA0-1]

Organism-specific databases

CTDi59341.
DisGeNETi59341.
GeneCardsiTRPV4.
GeneReviewsiTRPV4.
HGNCiHGNC:18083. TRPV4.
HPAiHPA007150.
MalaCardsiTRPV4.
MIMi113500. phenotype.
156530. phenotype.
168400. phenotype.
181405. phenotype.
184095. phenotype.
184252. phenotype.
600175. phenotype.
605427. gene.
606071. phenotype.
606835. phenotype.
613508. phenotype.
neXtProtiNX_Q9HBA0.
OpenTargetsiENSG00000111199.
Orphaneti93304. Autosomal dominant brachyolmia.
99937. Autosomal dominant Charcot-Marie-Tooth disease type 2C.
1216. Autosomal dominant congenital benign spinal muscular atrophy.
85169. Familial digital arthropathy-brachydactyly.
2635. Metatropic dysplasia.
2646. Parastremmatic dwarfism.
263482. Spondyloepiphyseal dysplasia, Maroteaux type.
93314. Spondylometaphyseal dysplasia, Kozlowski type.
PharmGKBiPA38293.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG3676. Eukaryota.
ENOG4110DG4. LUCA.
GeneTreeiENSGT00550000074425.
HOVERGENiHBG054085.
InParanoidiQ9HBA0.
KOiK04973.
OMAiKSETYQY.
OrthoDBiEOG091G016O.
PhylomeDBiQ9HBA0.
TreeFamiTF314711.

Enzyme and pathway databases

ReactomeiR-HSA-3295583. TRP channels.
SignaLinkiQ9HBA0.

Miscellaneous databases

GeneWikiiTRPV4.
GenomeRNAii59341.
PROiQ9HBA0.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000111199.
ExpressionAtlasiQ9HBA0. baseline and differential.
GenevisibleiQ9HBA0. HS.

Family and domain databases

Gene3Di1.25.40.20. 1 hit.
InterProiIPR002110. Ankyrin_rpt.
IPR020683. Ankyrin_rpt-contain_dom.
IPR005821. Ion_trans_dom.
IPR004729. TRP_channel.
IPR008347. TRPV1-4_channel.
IPR008348. TRPV4_channel.
[Graphical view]
PANTHERiPTHR10582:SF4. PTHR10582:SF4. 2 hits.
PfamiPF00023. Ank. 1 hit.
PF00520. Ion_trans. 1 hit.
[Graphical view]
PRINTSiPR01768. TRPVRECEPTOR.
PR01769. VRL2RECEPTOR.
SMARTiSM00248. ANK. 3 hits.
[Graphical view]
SUPFAMiSSF48403. SSF48403. 1 hit.
TIGRFAMsiTIGR00870. trp. 1 hit.
PROSITEiPS50297. ANK_REP_REGION. 1 hit.
PS50088. ANK_REPEAT. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiTRPV4_HUMAN
AccessioniPrimary (citable) accession number: Q9HBA0
Secondary accession number(s): B7ZKQ6
, Q17R79, Q2Y122, Q2Y123, Q2Y124, Q86YZ6, Q8NDY7, Q8NG64, Q96Q92, Q96RS7, Q9HBC0
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 26, 2005
Last sequence update: April 26, 2005
Last modified: November 2, 2016
This is version 143 of the entry and version 2 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, Reference proteome

Documents

  1. Human chromosome 12
    Human chromosome 12: 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.