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Protein

Histone deacetylase 3

Gene

HDAC3

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

Functioni

Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4), and some other non-histone substrates. Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Participates in the BCL6 transcriptional repressor activity by deacetylating the H3 'Lys-27' (H3K27) on enhancer elements, antagonizing EP300 acetyltransferase activity and repressing proximal gene expression. Probably participates in the regulation of transcription through its binding to the zinc-finger transcription factor YY1; increases YY1 repression activity. Required to repress transcription of the POU1F1 transcription factor. Acts as a molecular chaperone for shuttling phosphorylated NR2C1 to PML bodies for sumoylation (PubMed:21444723, PubMed:23911289). Contributes, together with XBP1 isoform 1, to the activation of NFE2L2-mediated HMOX1 transcription factor gene expression in a PI3K/mTORC2/Akt-dependent signaling pathway leading to endothelial cell (EC) survival under disturbed flow/oxidative stress (PubMed:25190803).3 Publications

Catalytic activityi

Hydrolysis of an N(6)-acetyl-lysine residue of a histone to yield a deacetylated histone.

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Active sitei135 – 1351By similarity

GO - Molecular functioni

  • chromatin binding Source: UniProtKB
  • cyclin binding Source: UniProtKB
  • enzyme binding Source: UniProtKB
  • histone deacetylase activity Source: UniProtKB
  • histone deacetylase binding Source: UniProtKB
  • NAD-dependent histone deacetylase activity (H3-K14 specific) Source: UniProtKB-EC
  • NF-kappaB binding Source: UniProtKB
  • protein deacetylase activity Source: UniProtKB
  • transcription corepressor activity Source: UniProtKB
  • transcription factor binding Source: UniProtKB

GO - Biological processi

  • cellular lipid metabolic process Source: Reactome
  • cellular response to fluid shear stress Source: UniProtKB
  • chromatin modification Source: UniProtKB
  • circadian rhythm Source: Reactome
  • negative regulation of apoptotic process Source: ProtInc
  • negative regulation of JNK cascade Source: UniProtKB
  • negative regulation of transcription, DNA-templated Source: UniProtKB
  • negative regulation of transcription from RNA polymerase II promoter Source: UniProtKB
  • positive regulation of protein phosphorylation Source: UniProtKB
  • positive regulation of TOR signaling Source: UniProtKB
  • positive regulation of transcription factor import into nucleus Source: UniProtKB
  • positive regulation of transcription from RNA polymerase II promoter Source: UniProtKB
  • protein deacetylation Source: UniProtKB
  • regulation of protein stability Source: UniProtKB
  • spindle assembly Source: UniProtKB
  • transcription, DNA-templated Source: UniProtKB-KW
Complete GO annotation...

Keywords - Molecular functioni

Chromatin regulator, Hydrolase, Repressor

Keywords - Biological processi

Transcription, Transcription regulation

Enzyme and pathway databases

ReactomeiR-HSA-1368071. NR1D1 (REV-ERBA) represses gene expression.
R-HSA-1368082. RORA activates gene expression.
R-HSA-1368108. BMAL1:CLOCK,NPAS2 activates circadian gene expression.
R-HSA-193670. p75NTR negatively regulates cell cycle via SC1.
R-HSA-1989781. PPARA activates gene expression.
R-HSA-2122947. NOTCH1 Intracellular Domain Regulates Transcription.
R-HSA-2151201. Transcriptional activation of mitochondrial biogenesis.
R-HSA-2644606. Constitutive Signaling by NOTCH1 PEST Domain Mutants.
R-HSA-2894862. Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants.
R-HSA-3214815. HDACs deacetylate histones.
R-HSA-381340. Transcriptional regulation of white adipocyte differentiation.
R-HSA-390471. Association of TriC/CCT with target proteins during biosynthesis.
R-HSA-400206. Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha).
R-HSA-400253. Circadian Clock.
R-HSA-5617472. Activation of anterior HOX genes in hindbrain development during early embryogenesis.
SABIO-RKO15379.
SignaLinkiO15379.
SIGNORiO15379.

Names & Taxonomyi

Protein namesi
Recommended name:
Histone deacetylase 3 (EC:3.5.1.98)
Short name:
HD3
Alternative name(s):
RPD3-2
SMAP45
Gene namesi
Name:HDAC3
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 5

Organism-specific databases

HGNCiHGNC:4854. HDAC3.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: UniProtKB
  • cytosol Source: UniProtKB
  • Golgi apparatus Source: HPA
  • histone deacetylase complex Source: UniProtKB
  • nucleoplasm Source: HPA
  • nucleus Source: UniProtKB
  • plasma membrane Source: HPA
  • spindle microtubule Source: UniProtKB
  • transcriptional repressor complex Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Organism-specific databases

PharmGKBiPA29228.

Chemistry

ChEMBLiCHEMBL2111363.
DrugBankiDB06603. Panobinostat.
DB02546. Vorinostat.
GuidetoPHARMACOLOGYi2617.

Polymorphism and mutation databases

BioMutaiHDAC3.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 428428Histone deacetylase 3PRO_0000114696Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Cross-linki44 – 44Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Modified residuei424 – 4241PhosphoserineCombined sources

Post-translational modificationi

Sumoylated in vitro.1 Publication

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiO15379.
MaxQBiO15379.
PaxDbiO15379.
PeptideAtlasiO15379.
PRIDEiO15379.

PTM databases

iPTMnetiO15379.
PhosphoSiteiO15379.

Miscellaneous databases

PMAP-CutDBO15379.

Expressioni

Tissue specificityi

Widely expressed.

Inductioni

Up-regulated by disturbed flow in umbilical vein endothelial cells in vitro (PubMed:25190803).

Gene expression databases

BgeeiENSG00000171720.
CleanExiHS_HDAC3.
ExpressionAtlasiO15379. baseline and differential.
GenevisibleiO15379. HS.

Organism-specific databases

HPAiCAB005583.
HPA052052.

Interactioni

Subunit structurei

Interacts with HDAC7 and HDAC9. Forms a heterologous complex at least with YY1. Interacts with DAXX, HDAC10 and DACH1. Found in a complex with NCOR1 and NCOR2. Component of the N-Cor repressor complex, at least composed of NCOR1, NCOR2, HDAC3, TBL1X, TBL1R, CORO2A and GPS2. Interacts with BCOR, MJD2A/JHDM3A, NRIP1, PRDM6 and SRY. Interacts with BTBD14B. Interacts with GLIS2. Interacts (via the DNA-binding domain) with NR2C1; the interaction recruits phosphorylated NR2C1 to PML bodies for sumoylation. Component of the Notch corepressor complex. Interacts with CBFA2T3 and NKAP. Interacts with APEX1; the interaction is not dependent on the acetylated status of APEX1. Interacts with and deacetylates MAPK14. Interacts with ZMYND15. Interacts with SMRT/NCOR2 and BCL6 on DNA enhancer elements. Interacts with INSM1 (PubMed:10655483, PubMed:10669754, PubMed:10860984, PubMed:10898795, PubMed:11006275, PubMed:11466315, PubMed:11533236, PubMed:11861901, PubMed:14525983, PubMed:14633989, PubMed:15297880, PubMed:15927959, PubMed:16569215, PubMed:18417529, PubMed:19409814, PubMed:23911289). Interacts with XBP1 isoform 1; the interaction occurs in endothelial cell (EC) under disturbed flow (PubMed:25190803). Interacts (via C-terminus) with CCAR2 (via N-terminus). Interacts with and deacetylates MEF2D. Interacts with BEND3.19 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
AKAP8O4382310EBI-607682,EBI-1237481
AKAP8LQ9ULX65EBI-607682,EBI-357530
APPL1Q9UKG12EBI-607682,EBI-741243
DHX30Q7L2E33EBI-607682,EBI-1211456
ICP0P083933EBI-607682,EBI-6148881From a different organism.
KDM1AO603414EBI-607682,EBI-710124
L3MBTL2Q969R56EBI-607682,EBI-739909
MAGEA2BP433564EBI-607682,EBI-5650739
MBD1Q9UIS93EBI-607682,EBI-867196
MYCP011066EBI-607682,EBI-447544
NCOR1O753765EBI-607682,EBI-347233
NR2E3Q9Y5X42EBI-607682,EBI-7216962
NRIP1P485522EBI-607682,EBI-746484
Nrip1Q8CBD12EBI-607682,EBI-1771626From a different organism.
PPP4CP605104EBI-607682,EBI-1046072
SUZ12Q150227EBI-607682,EBI-1264675
vifP125042EBI-607682,EBI-779991From a different organism.

GO - Molecular functioni

  • cyclin binding Source: UniProtKB
  • enzyme binding Source: UniProtKB
  • histone deacetylase binding Source: UniProtKB
  • NF-kappaB binding Source: UniProtKB
  • transcription factor binding Source: UniProtKB

Protein-protein interaction databases

BioGridi114368. 214 interactions.
DIPiDIP-24253N.
IntActiO15379. 74 interactions.
MINTiMINT-196172.
STRINGi9606.ENSP00000302967.

Chemistry

BindingDBiO15379.

Structurei

Secondary structure

1
428
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Beta strandi5 – 84Combined sources
Turni11 – 144Combined sources
Helixi27 – 3812Combined sources
Helixi41 – 444Combined sources
Beta strandi45 – 484Combined sources
Helixi55 – 584Combined sources
Turni59 – 613Combined sources
Helixi64 – 729Combined sources
Turni75 – 773Combined sources
Helixi78 – 814Combined sources
Helixi82 – 887Combined sources
Beta strandi91 – 944Combined sources
Helixi100 – 11920Combined sources
Beta strandi124 – 1285Combined sources
Beta strandi145 – 1473Combined sources
Helixi149 – 1579Combined sources
Turni158 – 1603Combined sources
Beta strandi164 – 1685Combined sources
Beta strandi170 – 1723Combined sources
Helixi175 – 1806Combined sources
Turni181 – 1833Combined sources
Beta strandi185 – 19410Combined sources
Helixi212 – 2143Combined sources
Beta strandi217 – 2237Combined sources
Helixi229 – 24719Combined sources
Beta strandi250 – 2556Combined sources
Helixi258 – 2603Combined sources
Helixi273 – 28412Combined sources
Beta strandi290 – 2934Combined sources
Helixi300 – 31415Combined sources
Helixi329 – 3324Combined sources
Turni333 – 3353Combined sources
Beta strandi337 – 3393Combined sources
Helixi352 – 36716Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
4A69X-ray2.06A/B1-376[»]
ProteinModelPortaliO15379.
SMRiO15379. Positions 2-370.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni3 – 316314Histone deacetylaseAdd
BLAST

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG1342. Eukaryota.
COG0123. LUCA.
GeneTreeiENSGT00530000062889.
HOGENOMiHOG000225180.
HOVERGENiHBG057112.
InParanoidiO15379.
KOiK11404.
OMAiQLNHKIC.
OrthoDBiEOG091G067J.
PhylomeDBiO15379.
TreeFamiTF352182.

Family and domain databases

Gene3Di3.40.800.20. 1 hit.
InterProiIPR000286. His_deacetylse.
IPR003084. His_deacetylse_1.
IPR023801. His_deacetylse_dom.
[Graphical view]
PANTHERiPTHR10625. PTHR10625. 1 hit.
PfamiPF00850. Hist_deacetyl. 1 hit.
[Graphical view]
PIRSFiPIRSF037913. His_deacetylse_1. 1 hit.
PRINTSiPR01270. HDASUPER.
PR01271. HISDACETLASE.

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: O15379-1) [UniParc]FASTAAdd to basket
Also known as: RPD3-2B

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
MAKTVAYFYD PDVGNFHYGA GHPMKPHRLA LTHSLVLHYG LYKKMIVFKP
60 70 80 90 100
YQASQHDMCR FHSEDYIDFL QRVSPTNMQG FTKSLNAFNV GDDCPVFPGL
110 120 130 140 150
FEFCSRYTGA SLQGATQLNN KICDIAINWA GGLHHAKKFE ASGFCYVNDI
160 170 180 190 200
VIGILELLKY HPRVLYIDID IHHGDGVQEA FYLTDRVMTV SFHKYGNYFF
210 220 230 240 250
PGTGDMYEVG AESGRYYCLN VPLRDGIDDQ SYKHLFQPVI NQVVDFYQPT
260 270 280 290 300
CIVLQCGADS LGCDRLGCFN LSIRGHGECV EYVKSFNIPL LVLGGGGYTV
310 320 330 340 350
RNVARCWTYE TSLLVEEAIS EELPYSEYFE YFAPDFTLHP DVSTRIENQN
360 370 380 390 400
SRQYLDQIRQ TIFENLKMLN HAPSVQIHDV PADLLTYDRT DEADAEERGP
410 420
EENYSRPEAP NEFYDGDHDN DKESDVEI
Length:428
Mass (Da):48,848
Last modified:July 15, 1998 - v2
Checksum:i94485C1EBDCF5AD0
GO
Isoform 2 (identifier: O15379-2) [UniParc]FASTAAdd to basket
Also known as: RPD3-2A

The sequence of this isoform differs from the canonical sequence as follows:
     1-15: MAKTVAYFYDPDVGN → MIVFKPYQASQHDMCR

Show »
Length:429
Mass (Da):49,111
Checksum:i0B654598513D284B
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti359 – 3591R → L in AAC52038 (PubMed:9464271).Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti411 – 4111N → S.
Corresponds to variant rs34901743 [ dbSNP | Ensembl ].
VAR_033988

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 1515MAKTV…PDVGN → MIVFKPYQASQHDMCR in isoform 2. 1 PublicationVSP_002079Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U66914 mRNA. Translation: AAC52038.1.
U75697 mRNA. Translation: AAB88241.1.
U75696 mRNA. Translation: AAB88240.1.
AF005482 mRNA. Translation: AAB87752.1.
AF039703 mRNA. Translation: AAC98927.1.
AF059650 Genomic DNA. Translation: AAC26509.1.
CH471062 Genomic DNA. Translation: EAW61915.1.
CH471062 Genomic DNA. Translation: EAW61916.1.
BC000614 mRNA. Translation: AAH00614.1.
AF053138, AF053137 Genomic DNA. Translation: AAC08351.1.
AF053139 Genomic DNA. Translation: AAC08352.1.
CCDSiCCDS4264.1. [O15379-1]
PIRiJC5834.
RefSeqiNP_003874.2. NM_003883.3. [O15379-1]
UniGeneiHs.519632.

Genome annotation databases

EnsembliENST00000305264; ENSP00000302967; ENSG00000171720. [O15379-1]
GeneIDi8841.
KEGGihsa:8841.
UCSCiuc003llf.3. human. [O15379-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Web resourcesi

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U66914 mRNA. Translation: AAC52038.1.
U75697 mRNA. Translation: AAB88241.1.
U75696 mRNA. Translation: AAB88240.1.
AF005482 mRNA. Translation: AAB87752.1.
AF039703 mRNA. Translation: AAC98927.1.
AF059650 Genomic DNA. Translation: AAC26509.1.
CH471062 Genomic DNA. Translation: EAW61915.1.
CH471062 Genomic DNA. Translation: EAW61916.1.
BC000614 mRNA. Translation: AAH00614.1.
AF053138, AF053137 Genomic DNA. Translation: AAC08351.1.
AF053139 Genomic DNA. Translation: AAC08352.1.
CCDSiCCDS4264.1. [O15379-1]
PIRiJC5834.
RefSeqiNP_003874.2. NM_003883.3. [O15379-1]
UniGeneiHs.519632.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
4A69X-ray2.06A/B1-376[»]
ProteinModelPortaliO15379.
SMRiO15379. Positions 2-370.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi114368. 214 interactions.
DIPiDIP-24253N.
IntActiO15379. 74 interactions.
MINTiMINT-196172.
STRINGi9606.ENSP00000302967.

Chemistry

BindingDBiO15379.
ChEMBLiCHEMBL2111363.
DrugBankiDB06603. Panobinostat.
DB02546. Vorinostat.
GuidetoPHARMACOLOGYi2617.

PTM databases

iPTMnetiO15379.
PhosphoSiteiO15379.

Polymorphism and mutation databases

BioMutaiHDAC3.

Proteomic databases

EPDiO15379.
MaxQBiO15379.
PaxDbiO15379.
PeptideAtlasiO15379.
PRIDEiO15379.

Protocols and materials databases

DNASUi8841.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000305264; ENSP00000302967; ENSG00000171720. [O15379-1]
GeneIDi8841.
KEGGihsa:8841.
UCSCiuc003llf.3. human. [O15379-1]

Organism-specific databases

CTDi8841.
GeneCardsiHDAC3.
HGNCiHGNC:4854. HDAC3.
HPAiCAB005583.
HPA052052.
MIMi605166. gene.
neXtProtiNX_O15379.
PharmGKBiPA29228.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG1342. Eukaryota.
COG0123. LUCA.
GeneTreeiENSGT00530000062889.
HOGENOMiHOG000225180.
HOVERGENiHBG057112.
InParanoidiO15379.
KOiK11404.
OMAiQLNHKIC.
OrthoDBiEOG091G067J.
PhylomeDBiO15379.
TreeFamiTF352182.

Enzyme and pathway databases

ReactomeiR-HSA-1368071. NR1D1 (REV-ERBA) represses gene expression.
R-HSA-1368082. RORA activates gene expression.
R-HSA-1368108. BMAL1:CLOCK,NPAS2 activates circadian gene expression.
R-HSA-193670. p75NTR negatively regulates cell cycle via SC1.
R-HSA-1989781. PPARA activates gene expression.
R-HSA-2122947. NOTCH1 Intracellular Domain Regulates Transcription.
R-HSA-2151201. Transcriptional activation of mitochondrial biogenesis.
R-HSA-2644606. Constitutive Signaling by NOTCH1 PEST Domain Mutants.
R-HSA-2894862. Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants.
R-HSA-3214815. HDACs deacetylate histones.
R-HSA-381340. Transcriptional regulation of white adipocyte differentiation.
R-HSA-390471. Association of TriC/CCT with target proteins during biosynthesis.
R-HSA-400206. Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha).
R-HSA-400253. Circadian Clock.
R-HSA-5617472. Activation of anterior HOX genes in hindbrain development during early embryogenesis.
SABIO-RKO15379.
SignaLinkiO15379.
SIGNORiO15379.

Miscellaneous databases

ChiTaRSiHDAC3. human.
GeneWikiiHDAC3.
GenomeRNAii8841.
PMAP-CutDBO15379.
PROiO15379.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000171720.
CleanExiHS_HDAC3.
ExpressionAtlasiO15379. baseline and differential.
GenevisibleiO15379. HS.

Family and domain databases

Gene3Di3.40.800.20. 1 hit.
InterProiIPR000286. His_deacetylse.
IPR003084. His_deacetylse_1.
IPR023801. His_deacetylse_dom.
[Graphical view]
PANTHERiPTHR10625. PTHR10625. 1 hit.
PfamiPF00850. Hist_deacetyl. 1 hit.
[Graphical view]
PIRSFiPIRSF037913. His_deacetylse_1. 1 hit.
PRINTSiPR01270. HDASUPER.
PR01271. HISDACETLASE.
ProtoNetiSearch...

Entry informationi

Entry nameiHDAC3_HUMAN
AccessioniPrimary (citable) accession number: O15379
Secondary accession number(s): D3DQE1
, O43268, Q9UEI5, Q9UEV0
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 15, 1998
Last sequence update: July 15, 1998
Last modified: September 7, 2016
This is version 181 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 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.