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Protein

Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4

Gene

HCN4

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

Functioni

Hyperpolarization-activated ion channel with very slow activation and inactivation exhibiting weak selectivity for potassium over sodium ions. Contributes to the native pacemaker currents in heart (If) that regulate the rhythm of heart beat. May contribute to the native pacemaker currents in neurons (Ih). May mediate responses to sour stimuli.5 Publications

Enzyme regulationi

Activated by cAMP. cAMP binding causes a conformation change that leads to the assembly of an active tetramer and channel opening.3 Publications

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi659 – 662cAMP2 Publications4
Nucleotide bindingi669 – 670cAMP2 Publications2
Nucleotide bindingi710 – 713cAMP2 Publications4

GO - Molecular functioni

  • cAMP binding Source: UniProtKB-KW
  • intracellular cAMP activated cation channel activity Source: UniProtKB
  • voltage-gated potassium channel activity Source: UniProtKB
  • voltage-gated sodium channel activity Source: UniProtKB

GO - Biological processi

  • blood circulation Source: ProtInc
  • cation transport Source: BHF-UCL
  • cellular response to cAMP Source: UniProtKB
  • cellular response to cGMP Source: UniProtKB
  • muscle contraction Source: ProtInc
  • potassium ion transmembrane transport Source: UniProtKB
  • regulation of cardiac muscle contraction Source: BHF-UCL
  • regulation of heart rate Source: UniProtKB
  • regulation of heart rate by cardiac conduction Source: BHF-UCL
  • regulation of membrane depolarization Source: BHF-UCL
  • regulation of membrane potential Source: UniProtKB
  • SA node cell action potential Source: BHF-UCL
  • sodium ion transmembrane transport Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Ion channel, Ligand-gated ion channel, Potassium channel, Sodium channel, Voltage-gated channel

Keywords - Biological processi

Ion transport, Potassium transport, Sodium transport, Transport

Keywords - Ligandi

cAMP, cAMP-binding, Nucleotide-binding, Potassium, Sodium

Enzyme and pathway databases

BioCyciZFISH:ENSG00000138622-MONOMER.
ReactomeiR-HSA-1296061. HCN channels.
SIGNORiQ9Y3Q4.

Protein family/group databases

TCDBi1.A.1.5.10. the voltage-gated ion channel (vic) superfamily.
1.A.1.5.11. the voltage-gated ion channel (vic) superfamily.

Names & Taxonomyi

Protein namesi
Recommended name:
Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4
Gene namesi
Name:HCN4
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 15

Organism-specific databases

HGNCiHGNC:16882. HCN4.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 266CytoplasmicSequence analysisAdd BLAST266
Transmembranei267 – 287Helical; Name=Segment S1Sequence analysisAdd BLAST21
Topological domaini288 – 293ExtracellularSequence analysis6
Transmembranei294 – 314Helical; Name=Segment S2Sequence analysisAdd BLAST21
Topological domaini315 – 340CytoplasmicSequence analysisAdd BLAST26
Transmembranei341 – 361Helical; Name=Segment S3Sequence analysisAdd BLAST21
Topological domaini362 – 368ExtracellularSequence analysis7
Transmembranei369 – 389Helical; Voltage-sensor; Name=Segment S4Sequence analysisAdd BLAST21
Topological domaini390 – 420CytoplasmicSequence analysisAdd BLAST31
Transmembranei421 – 441Helical; Name=Segment S5Sequence analysisAdd BLAST21
Topological domaini442 – 464ExtracellularSequence analysisAdd BLAST23
Intramembranei465 – 486Pore-forming; Name=Segment H5Sequence analysisAdd BLAST22
Topological domaini487 – 496ExtracellularSequence analysis10
Transmembranei497 – 517Helical; Name=Segment S6Sequence analysisAdd BLAST21
Topological domaini518 – 1203CytoplasmicSequence analysisAdd BLAST686

GO - Cellular componenti

  • integral component of plasma membrane Source: GO_Central
  • intrinsic component of plasma membrane Source: UniProtKB
  • perinuclear region of cytoplasm Source: BHF-UCL
  • plasma membrane Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Involvement in diseasei

Sick sinus syndrome 2 (SSS2)3 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionThe term 'sick sinus syndrome' encompasses a variety of conditions caused by sinus node dysfunction. The most common clinical manifestations are syncope, presyncope, dizziness, and fatigue. Electrocardiogram typically shows sinus bradycardia, sinus arrest, and/or sinoatrial block. Episodes of atrial tachycardias coexisting with sinus bradycardia ('tachycardia-bradycardia syndrome') are also common in this disorder. SSS occurs most often in the elderly associated with underlying heart disease or previous cardiac surgery, but can also occur in the fetus, infant, or child without heart disease or other contributing factors. SSS2 onset is in utero or at birth.
See also OMIM:163800
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_066614485A → V in SSS2; results in a significant reduction of current density compared to wild-type. 1 Publication1
Natural variantiVAR_026534553D → N in SSS2. 1 PublicationCorresponds to variant rs104894485dbSNPEnsembl.1
Natural variantiVAR_026535672S → R in SSS2; results in decreased affinity for cAMP but does not abolish channel activation; shifts the current activation range to hyperpolarized voltages; slows channel opening and speeds up channel closure. 2 PublicationsCorresponds to variant rs104894488dbSNPEnsembl.1
Brugada syndrome 8 (BRGDA8)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs, the individual will faint and may die in a few minutes if the heart is not reset.
See also OMIM:613123

Keywords - Diseasei

Brugada syndrome, Disease mutation

Organism-specific databases

DisGeNETi10021.
MalaCardsiHCN4.
MIMi163800. phenotype.
613123. phenotype.
OpenTargetsiENSG00000138622.
Orphaneti130. Brugada syndrome.
166282. Familial sick sinus syndrome.
PharmGKBiPA394.

Chemistry databases

ChEMBLiCHEMBL1250417.
GuidetoPHARMACOLOGYi403.

Polymorphism and mutation databases

BioMutaiHCN4.
DMDMi38605641.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000541171 – 1203Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4Add BLAST1203

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei138PhosphoserineBy similarity1
Glycosylationi458N-linked (GlcNAc...)Sequence analysis1
Modified residuei1105PhosphoserineBy similarity1
Modified residuei1108PhosphoserineBy similarity1

Keywords - PTMi

Glycoprotein, Phosphoprotein

Proteomic databases

EPDiQ9Y3Q4.
MaxQBiQ9Y3Q4.
PaxDbiQ9Y3Q4.
PeptideAtlasiQ9Y3Q4.
PRIDEiQ9Y3Q4.

PTM databases

iPTMnetiQ9Y3Q4.
PhosphoSitePlusiQ9Y3Q4.

Expressioni

Tissue specificityi

Highly expressed in thalamus, testis and in heart, both in ventricle and atrium. Detected at much lower levels in amygdala, substantia nigra, cerebellum and hippocampus.2 Publications

Gene expression databases

BgeeiENSG00000138622.
CleanExiHS_HCN4.
GenevisibleiQ9Y3Q4. HS.

Organism-specific databases

HPAiCAB026135.

Interactioni

Subunit structurei

Homotetramer. The potassium channel is composed of a homo- or heterotetrameric complex of pore-forming subunits.2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
itself2EBI-1753521,EBI-1753521

Protein-protein interaction databases

BioGridi115338. 3 interactors.
DIPiDIP-52325N.
IntActiQ9Y3Q4. 2 interactors.
STRINGi9606.ENSP00000261917.

Chemistry databases

BindingDBiQ9Y3Q4.

Structurei

Secondary structure

11203
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi522 – 540Combined sources19
Helixi545 – 559Combined sources15
Helixi566 – 571Combined sources6
Helixi575 – 585Combined sources11
Helixi587 – 591Combined sources5
Helixi594 – 597Combined sources4
Helixi601 – 608Combined sources8
Beta strandi612 – 616Combined sources5
Beta strandi621 – 623Combined sources3
Beta strandi631 – 637Combined sources7
Beta strandi640 – 643Combined sources4
Beta strandi645 – 647Combined sources3
Beta strandi650 – 652Combined sources3
Helixi661 – 665Combined sources5
Beta strandi666 – 668Combined sources3
Beta strandi670 – 677Combined sources8
Beta strandi679 – 685Combined sources7
Helixi686 – 695Combined sources10
Helixi697 – 699Combined sources3
Helixi700 – 712Combined sources13

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2MNGNMR-A579-707[»]
3OTFX-ray2.40A521-739[»]
3U11X-ray2.50A/B521-723[»]
4HBNX-ray2.60A521-724[»]
4KL1X-ray2.70A/B/C/D521-713[»]
4NVPX-ray2.50A521-723[»]
ProteinModelPortaliQ9Y3Q4.
SMRiQ9Y3Q4.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ9Y3Q4.

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni209 – 260Involved in subunit assemblyBy similarityAdd BLAST52

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi924 – 1076Pro-richAdd BLAST153

Domaini

The segment S4 is probably the voltage-sensor and is characterized by a series of positively charged amino acids at every third position.

Sequence similaritiesi

Belongs to the potassium channel HCN family.Curated
Contains 1 cyclic nucleotide-binding domain.PROSITE-ProRule annotation

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG0498. Eukaryota.
ENOG410XPSE. LUCA.
GeneTreeiENSGT00760000118772.
HOGENOMiHOG000230717.
HOVERGENiHBG039490.
InParanoidiQ9Y3Q4.
KOiK04957.
OMAiGAIPGQH.
OrthoDBiEOG091G0JQU.
PhylomeDBiQ9Y3Q4.
TreeFamiTF318250.

Family and domain databases

Gene3Di2.60.120.10. 1 hit.
InterProiIPR018490. cNMP-bd-like.
IPR018488. cNMP-bd_CS.
IPR000595. cNMP-bd_dom.
IPR030173. HCN4.
IPR005821. Ion_trans_dom.
IPR013621. Ion_trans_N.
IPR003938. K_chnl_volt-dep_EAG/ELK/ERG.
IPR014710. RmlC-like_jellyroll.
[Graphical view]
PANTHERiPTHR10217:SF375. PTHR10217:SF375. 3 hits.
PfamiPF00027. cNMP_binding. 1 hit.
PF00520. Ion_trans. 1 hit.
PF08412. Ion_trans_N. 1 hit.
[Graphical view]
PRINTSiPR01463. EAGCHANLFMLY.
SMARTiSM00100. cNMP. 1 hit.
[Graphical view]
SUPFAMiSSF51206. SSF51206. 1 hit.
PROSITEiPS00888. CNMP_BINDING_1. 1 hit.
PS50042. CNMP_BINDING_3. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q9Y3Q4-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MDKLPPSMRK RLYSLPQQVG AKAWIMDEEE DAEEEGAGGR QDPSRRSIRL
60 70 80 90 100
RPLPSPSPSA AAGGTESRSS ALGAADSEGP ARGAGKSSTN GDCRRFRGSL
110 120 130 140 150
ASLGSRGGGS GGTGSGSSHG HLHDSAEERR LIAEGDASPG EDRTPPGLAA
160 170 180 190 200
EPERPGASAQ PAASPPPPQQ PPQPASASCE QPSVDTAIKV EGGAAAGDQI
210 220 230 240 250
LPEAEVRLGQ AGFMQRQFGA MLQPGVNKFS LRMFGSQKAV EREQERVKSA
260 270 280 290 300
GFWIIHPYSD FRFYWDLTML LLMVGNLIII PVGITFFKDE NTTPWIVFNV
310 320 330 340 350
VSDTFFLIDL VLNFRTGIVV EDNTEIILDP QRIKMKYLKS WFMVDFISSI
360 370 380 390 400
PVDYIFLIVE TRIDSEVYKT ARALRIVRFT KILSLLRLLR LSRLIRYIHQ
410 420 430 440 450
WEEIFHMTYD LASAVVRIVN LIGMMLLLCH WDGCLQFLVP MLQDFPDDCW
460 470 480 490 500
VSINNMVNNS WGKQYSYALF KAMSHMLCIG YGRQAPVGMS DVWLTMLSMI
510 520 530 540 550
VGATCYAMFI GHATALIQSL DSSRRQYQEK YKQVEQYMSF HKLPPDTRQR
560 570 580 590 600
IHDYYEHRYQ GKMFDEESIL GELSEPLREE IINFNCRKLV ASMPLFANAD
610 620 630 640 650
PNFVTSMLTK LRFEVFQPGD YIIREGTIGK KMYFIQHGVV SVLTKGNKET
660 670 680 690 700
KLADGSYFGE ICLLTRGRRT ASVRADTYCR LYSLSVDNFN EVLEEYPMMR
710 720 730 740 750
RAFETVALDR LDRIGKKNSI LLHKVQHDLN SGVFNYQENE IIQQIVQHDR
760 770 780 790 800
EMAHCAHRVQ AAASATPTPT PVIWTPLIQA PLQAAAATTS VAIALTHHPR
810 820 830 840 850
LPAAIFRPPP GSGLGNLGAG QTPRHLKRLQ SLIPSALGSA SPASSPSQVD
860 870 880 890 900
TPSSSSFHIQ QLAGFSAPAG LSPLLPSSSS SPPPGACGSP SAPTPSAGVA
910 920 930 940 950
ATTIAGFGHF HKALGGSLSS SDSPLLTPLQ PGARSPQAAQ PSPAPPGARG
960 970 980 990 1000
GLGLPEHFLP PPPSSRSPSS SPGQLGQPPG ELSLGLATGP LSTPETPPRQ
1010 1020 1030 1040 1050
PEPPSLVAGA SGGASPVGFT PRGGLSPPGH SPGPPRTFPS APPRASGSHG
1060 1070 1080 1090 1100
SLLLPPASSP PPPQVPQRRG TPPLTPGRLT QDLKLISASQ PALPQDGAQT
1110 1120 1130 1140 1150
LRRASPHSSG ESMAAFPLFP RAGGGSGGSG SSGGLGPPGR PYGAIPGQHV
1160 1170 1180 1190 1200
TLPRKTSSGS LPPPLSLFGA RATSSGGPPL TAGPQREPGA RPEPVRSKLP

SNL
Length:1,203
Mass (Da):129,042
Last modified:November 1, 1999 - v1
Checksum:i7EFDD2D69CF1F9D9
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti110S → T in CAB52754 (PubMed:10430953).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_066614485A → V in SSS2; results in a significant reduction of current density compared to wild-type. 1 Publication1
Natural variantiVAR_026534553D → N in SSS2. 1 PublicationCorresponds to variant rs104894485dbSNPEnsembl.1
Natural variantiVAR_026535672S → R in SSS2; results in decreased affinity for cAMP but does not abolish channel activation; shifts the current activation range to hyperpolarized voltages; slows channel opening and speeds up channel closure. 2 PublicationsCorresponds to variant rs104894488dbSNPEnsembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AJ132429 mRNA. Translation: CAB42604.1.
AJ238850 mRNA. Translation: CAB52754.1.
CCDSiCCDS10248.1.
RefSeqiNP_005468.1. NM_005477.2.
UniGeneiHs.86941.

Genome annotation databases

EnsembliENST00000261917; ENSP00000261917; ENSG00000138622.
GeneIDi10021.
KEGGihsa:10021.
UCSCiuc002avp.3. human.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AJ132429 mRNA. Translation: CAB42604.1.
AJ238850 mRNA. Translation: CAB52754.1.
CCDSiCCDS10248.1.
RefSeqiNP_005468.1. NM_005477.2.
UniGeneiHs.86941.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2MNGNMR-A579-707[»]
3OTFX-ray2.40A521-739[»]
3U11X-ray2.50A/B521-723[»]
4HBNX-ray2.60A521-724[»]
4KL1X-ray2.70A/B/C/D521-713[»]
4NVPX-ray2.50A521-723[»]
ProteinModelPortaliQ9Y3Q4.
SMRiQ9Y3Q4.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi115338. 3 interactors.
DIPiDIP-52325N.
IntActiQ9Y3Q4. 2 interactors.
STRINGi9606.ENSP00000261917.

Chemistry databases

BindingDBiQ9Y3Q4.
ChEMBLiCHEMBL1250417.
GuidetoPHARMACOLOGYi403.

Protein family/group databases

TCDBi1.A.1.5.10. the voltage-gated ion channel (vic) superfamily.
1.A.1.5.11. the voltage-gated ion channel (vic) superfamily.

PTM databases

iPTMnetiQ9Y3Q4.
PhosphoSitePlusiQ9Y3Q4.

Polymorphism and mutation databases

BioMutaiHCN4.
DMDMi38605641.

Proteomic databases

EPDiQ9Y3Q4.
MaxQBiQ9Y3Q4.
PaxDbiQ9Y3Q4.
PeptideAtlasiQ9Y3Q4.
PRIDEiQ9Y3Q4.

Protocols and materials databases

DNASUi10021.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000261917; ENSP00000261917; ENSG00000138622.
GeneIDi10021.
KEGGihsa:10021.
UCSCiuc002avp.3. human.

Organism-specific databases

CTDi10021.
DisGeNETi10021.
GeneCardsiHCN4.
GeneReviewsiHCN4.
HGNCiHGNC:16882. HCN4.
HPAiCAB026135.
MalaCardsiHCN4.
MIMi163800. phenotype.
605206. gene.
613123. phenotype.
neXtProtiNX_Q9Y3Q4.
OpenTargetsiENSG00000138622.
Orphaneti130. Brugada syndrome.
166282. Familial sick sinus syndrome.
PharmGKBiPA394.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0498. Eukaryota.
ENOG410XPSE. LUCA.
GeneTreeiENSGT00760000118772.
HOGENOMiHOG000230717.
HOVERGENiHBG039490.
InParanoidiQ9Y3Q4.
KOiK04957.
OMAiGAIPGQH.
OrthoDBiEOG091G0JQU.
PhylomeDBiQ9Y3Q4.
TreeFamiTF318250.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000138622-MONOMER.
ReactomeiR-HSA-1296061. HCN channels.
SIGNORiQ9Y3Q4.

Miscellaneous databases

EvolutionaryTraceiQ9Y3Q4.
GeneWikiiHCN4.
GenomeRNAii10021.
PROiQ9Y3Q4.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000138622.
CleanExiHS_HCN4.
GenevisibleiQ9Y3Q4. HS.

Family and domain databases

Gene3Di2.60.120.10. 1 hit.
InterProiIPR018490. cNMP-bd-like.
IPR018488. cNMP-bd_CS.
IPR000595. cNMP-bd_dom.
IPR030173. HCN4.
IPR005821. Ion_trans_dom.
IPR013621. Ion_trans_N.
IPR003938. K_chnl_volt-dep_EAG/ELK/ERG.
IPR014710. RmlC-like_jellyroll.
[Graphical view]
PANTHERiPTHR10217:SF375. PTHR10217:SF375. 3 hits.
PfamiPF00027. cNMP_binding. 1 hit.
PF00520. Ion_trans. 1 hit.
PF08412. Ion_trans_N. 1 hit.
[Graphical view]
PRINTSiPR01463. EAGCHANLFMLY.
SMARTiSM00100. cNMP. 1 hit.
[Graphical view]
SUPFAMiSSF51206. SSF51206. 1 hit.
PROSITEiPS00888. CNMP_BINDING_1. 1 hit.
PS50042. CNMP_BINDING_3. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiHCN4_HUMAN
AccessioniPrimary (citable) accession number: Q9Y3Q4
Secondary accession number(s): Q9UMQ7
Entry historyi
Integrated into UniProtKB/Swiss-Prot: February 28, 2003
Last sequence update: November 1, 1999
Last modified: November 2, 2016
This is version 147 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

Miscellaneous

Inhibited by extracellular cesium ions.

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 15
    Human chromosome 15: 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.