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Protein

Forkhead box protein O3

Gene

Foxo3

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Transcriptional activator which triggers apoptosis in the absence of survival factors, including neuronal cell death upon oxidative stress. Recognizes and binds to the DNA sequence 5'-[AG]TAAA[TC]A-3'. Participates in post-transcriptional regulation of MYC: following phosphorylation by MAPKAPK5, promotes induction of miR-34b and miR-34c expression, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent its translation (By similarity).By similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
DNA bindingi156 – 25095Fork-headPROSITE-ProRule annotationAdd
BLAST

GO - Molecular functioni

  • chromatin DNA binding Source: UniProtKB
  • core promoter binding Source: UniProtKB
  • DNA binding Source: MGI
  • protein kinase binding Source: MGI
  • RNA polymerase II transcription regulatory region sequence-specific DNA binding transcription factor activity involved in negative regulation of transcription Source: MGI
  • sequence-specific DNA binding Source: MGI
  • sequence-specific DNA binding transcription factor activity Source: MGI

GO - Biological processi

  • anatomical structure morphogenesis Source: GO_Central
  • antral ovarian follicle growth Source: MGI
  • cell differentiation Source: GO_Central
  • cellular response to oxidative stress Source: UniProtKB
  • DNA damage response, signal transduction by p53 class mediator Source: MGI
  • extrinsic apoptotic signaling pathway in absence of ligand Source: MGI
  • glucose homeostasis Source: MGI
  • initiation of primordial ovarian follicle growth Source: MGI
  • negative regulation of canonical Wnt signaling pathway Source: MGI
  • negative regulation of transcription from RNA polymerase II promoter Source: MGI
  • neuronal stem cell maintenance Source: MGI
  • oocyte maturation Source: MGI
  • ovulation from ovarian follicle Source: MGI
  • positive regulation of erythrocyte differentiation Source: MGI
  • positive regulation of neuron apoptotic process Source: MGI
  • positive regulation of transcription, DNA-templated Source: MGI
  • positive regulation of transcription from RNA polymerase II promoter Source: BHF-UCL
  • regulation of neural precursor cell proliferation Source: MGI
  • regulation of reactive oxygen species metabolic process Source: MGI
  • regulation of transcription, DNA-templated Source: MGI
  • regulation of transcription from RNA polymerase II promoter Source: UniProtKB
  • regulation of translation Source: UniProtKB
  • transcription, DNA-templated Source: UniProtKB-KW
Complete GO annotation...

Keywords - Molecular functioni

Activator

Keywords - Biological processi

Apoptosis, Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding

Enzyme and pathway databases

ReactomeiREACT_308448. AKT phosphorylates targets in the nucleus.
REACT_331083. Signaling by NODAL.

Names & Taxonomyi

Protein namesi
Recommended name:
Forkhead box protein O3
Gene namesi
Name:Foxo3
Synonyms:Fkhr2, Foxo3a
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589 Componenti: Chromosome 10

Organism-specific databases

MGIiMGI:1890081. Foxo3.

Subcellular locationi

  • Cytoplasmcytosol By similarity
  • Nucleus PROSITE-ProRule annotation

  • Note: Translocates to the nucleus upon oxidative stress and in the absence of survival factors.By similarity

GO - Cellular componenti

  • cytoplasm Source: MGI
  • cytosol Source: UniProtKB-SubCell
  • membrane Source: MGI
  • nucleoplasm Source: MGI
  • nucleus Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Keywords - Diseasei

Proto-oncogene

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 672672Forkhead box protein O3PRO_0000415334Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei32 – 321Phosphothreonine; by PKB/AKT1By similarity
Modified residuei46 – 461N6-methyllysineBy similarity
Modified residuei148 – 1481N6-methyllysineBy similarity
Modified residuei178 – 1781Phosphothreonine; by AMPKBy similarity
Modified residuei208 – 2081Phosphoserine; by STK4/MST1By similarity
Modified residuei214 – 2141Phosphoserine; by MAPKAPK5By similarity
Modified residuei229 – 2291N6-methyllysineBy similarity
Modified residuei241 – 2411N6-acetyllysine1 Publication
Modified residuei252 – 2521Phosphoserine; by PKB/AKT1 and MAPKAPK5By similarity
Modified residuei261 – 2611N6-methyllysineBy similarity
Modified residuei270 – 2701N6-methyllysineBy similarity
Modified residuei279 – 2791PhosphoserineBy similarity
Modified residuei283 – 2831PhosphoserineBy similarity
Modified residuei289 – 2891N6-methyllysineBy similarity
Modified residuei314 – 3141Phosphoserine; by SGK1By similarity
Modified residuei398 – 3981Phosphoserine; by AMPKBy similarity
Modified residuei412 – 4121Phosphoserine; by AMPKBy similarity
Modified residuei418 – 4181N6-methyllysineBy similarity
Modified residuei420 – 4201PhosphoserineBy similarity
Modified residuei550 – 5501Phosphoserine; by MAPKAPK5By similarity
Modified residuei554 – 5541Phosphoserine; by AMPK and MAPKAPK5By similarity
Modified residuei587 – 5871Phosphoserine; by AMPKBy similarity
Modified residuei625 – 6251Phosphoserine; by AMPKBy similarity

Post-translational modificationi

Deacetylation by SIRT1 or SIRT2 stimulates interaction of FOXO3 with SKP2 and facilitates SCF(SKP2)-mediated FOXO3 ubiquitination and proteasomal degradation (By similarity). Deacetylation by SIRT2 stimulates FOXO3-mediated transcriptional activity in response to oxidative stress.By similarity
In the presence of survival factors such as IGF-1, phosphorylated on Thr-32 and Ser-252 by AKT1/PKB. This phosphorylated form then interacts with 14-3-3 proteins and is retained in the cytoplasm. Survival factor withdrawal induces dephosphorylation and promotes translocation to the nucleus where the dephosphorylated protein induces transcription of target genes and triggers apoptosis. Although AKT1/PKB doesn't appear to phosphorylate Ser-314 directly, it may activate other kinases that trigger phosphorylation at this residue. Phosphorylated by STK4/MST1 on Ser-208 upon oxidative stress, which leads to dissociation from YWHAB/14-3-3-beta and nuclear translocation. Phosphorylated by PIM1. Phosphorylation by AMPK leads to the activation of transcriptional activity without affecting subcellular localization. Phosphorylation by MAPKAPK5 promotes nuclear localization and DNA-binding, leading to induction of miR-34b and miR-34c expression, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent its translation (By similarity).By similarity
Heavyly methylated by SET9 which decreases stability, while moderately increasing transcriptional activity. The main methylation site is Lys-270. Methylation doesn't affect subcellular location (By similarity).By similarity
Polyubiquitinated. Ubiquitinated by a SCF complex containing SKP2, leading to proteasomal degradation (By similarity).By similarity

Keywords - PTMi

Acetylation, Methylation, Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiQ9WVH4.
PRIDEiQ9WVH4.

PTM databases

PhosphoSiteiQ9WVH4.

Expressioni

Tissue specificityi

Expressed in white and brown adipose tissues (at protein level).1 Publication

Gene expression databases

BgeeiQ9WVH4.
ExpressionAtlasiQ9WVH4. baseline and differential.
GenevisibleiQ9WVH4. MM.

Interactioni

Subunit structurei

Interacts with YWHAB/14-3-3-beta and YWHAZ/14-3-3-zeta, which are required for cytosolic sequestration. Upon oxidative stress, interacts with STK4/MST1, which disrupts interaction with YWHAB/14-3-3-beta and leads to nuclear translocation. Interacts with PIM1. Interacts with DDIT3/CHOP. Interacts (deacetylated form) with SKP2 (By similarity). Interacts with SIRT2; the interaction occurs independently of SIRT2 deacetylase activity.By similarity1 Publication

Binary interactionsi

WithEntry#Exp.IntActNotes
FcorP0DJI62EBI-6127038,EBI-6126630
SETD7Q8WTS65EBI-6127038,EBI-1268586From a different organism.

Protein-protein interaction databases

BioGridi208010. 5 interactions.
IntActiQ9WVH4. 2 interactions.
STRINGi10090.ENSMUSP00000050683.

Structurei

3D structure databases

ProteinModelPortaliQ9WVH4.
SMRiQ9WVH4. Positions 157-252.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi241 – 25818Nuclear localization signalBy similarityAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi546 – 59550Ser-richAdd
BLAST

Sequence similaritiesi

Contains 1 fork-head DNA-binding domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiCOG5025.
GeneTreeiENSGT00790000123003.
HOGENOMiHOG000169927.
HOVERGENiHBG078744.
InParanoidiQ9WVH4.
KOiK09408.
OMAiWMINPDG.
OrthoDBiEOG7R2BJD.
PhylomeDBiQ9WVH4.
TreeFamiTF315583.

Family and domain databases

Gene3Di1.10.10.10. 1 hit.
InterProiIPR001766. TF_fork_head.
IPR011991. WHTH_DNA-bd_dom.
[Graphical view]
PfamiPF00250. Fork_head. 1 hit.
[Graphical view]
PRINTSiPR00053. FORKHEAD.
SMARTiSM00339. FH. 1 hit.
[Graphical view]
PROSITEiPS00658. FORK_HEAD_2. 1 hit.
PS50039. FORK_HEAD_3. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q9WVH4-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MAEAPASPVP LSPLEVELDP EFEPQSRPRS CTWPLQRPEL QASPAKPSGE
60 70 80 90 100
TAADSMIPEE DDDEDDEDGG GRASSAMVIG GGVSSTLGSG LLLEDSAMLL
110 120 130 140 150
APGGQDLGSG PASAAGALSG GTPTQLQPQQ PLPQPQPGAA GGSGQPRKCS
160 170 180 190 200
SRRNAWGNLS YADLITRAIE SSPDKRLTLS QIYEWMVRCV PYFKDKGDSN
210 220 230 240 250
SSAGWKNSIR HNLSLHSRFM RVQNEGTGKS SWWIINPDGG KSGKAPRRRA
260 270 280 290 300
VSMDNSNKYT KSRGRAAKKK AALQAAPESA DDSPSQLSKW PGSPTSRSSD
310 320 330 340 350
ELDAWTDFRS RTNSNASTVS GRLSPILAST ELDDVQDDDG PLSPMLYSSS
360 370 380 390 400
ASLSPSVSKP CTVELPRLTD MAGTMNLNDG LAENLMDDLL DNIALPPSQP
410 420 430 440 450
SPPGGLMQRG SSFPYTAKSS GLGSPTGSFN STVFGPSSLN SLRQSPMQTI
460 470 480 490 500
QENRPATFSS VSHYGNQTLQ DLLASDSLSH SDVMMTQSDP LMSQASTAVS
510 520 530 540 550
AQNARRNVML RNDPMMSFAA QPTQGSLVNQ NLLHHQHQTQ GALGGSRALS
560 570 580 590 600
NSVSNMGLSD SSSLGSAKHQ QQSPASQSMQ TLSDSLSGSS LYSASANLPV
610 620 630 640 650
MGHDKFPSDL DLDMFNGSLE CDMESIIRSE LMDADGLDFN FDSLISTQNV
660 670
VGLNVGNFTG AKQASSQSWV PG
Length:672
Mass (Da):71,064
Last modified:November 1, 1999 - v1
Checksum:iEC218D9BA0C1DAC5
GO

Sequence cautioni

The sequence AAH19532.1 differs from that shown.Contaminating sequence. Potential poly-A sequence.Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF114259 mRNA. Translation: AAD42107.1.
AK047413 mRNA. Translation: BAC33049.1.
AC116179 Genomic DNA. No translation available.
AC140402 Genomic DNA. No translation available.
CH466540 Genomic DNA. Translation: EDL04998.1.
BC019532 mRNA. Translation: AAH19532.1. Sequence problems.
CCDSiCCDS23810.1.
RefSeqiNP_062714.1. NM_019740.2.
XP_006512869.1. XM_006512806.1.
UniGeneiMm.338613.
Mm.391700.
Mm.417859.
Mm.466459.

Genome annotation databases

EnsembliENSMUST00000056974; ENSMUSP00000050683; ENSMUSG00000048756.
ENSMUST00000105502; ENSMUSP00000101141; ENSMUSG00000048756.
ENSMUST00000175881; ENSMUSP00000135380; ENSMUSG00000048756.
GeneIDi56484.
KEGGimmu:56484.
UCSCiuc007eyl.1. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF114259 mRNA. Translation: AAD42107.1.
AK047413 mRNA. Translation: BAC33049.1.
AC116179 Genomic DNA. No translation available.
AC140402 Genomic DNA. No translation available.
CH466540 Genomic DNA. Translation: EDL04998.1.
BC019532 mRNA. Translation: AAH19532.1. Sequence problems.
CCDSiCCDS23810.1.
RefSeqiNP_062714.1. NM_019740.2.
XP_006512869.1. XM_006512806.1.
UniGeneiMm.338613.
Mm.391700.
Mm.417859.
Mm.466459.

3D structure databases

ProteinModelPortaliQ9WVH4.
SMRiQ9WVH4. Positions 157-252.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi208010. 5 interactions.
IntActiQ9WVH4. 2 interactions.
STRINGi10090.ENSMUSP00000050683.

PTM databases

PhosphoSiteiQ9WVH4.

Proteomic databases

MaxQBiQ9WVH4.
PRIDEiQ9WVH4.

Protocols and materials databases

DNASUi56484.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000056974; ENSMUSP00000050683; ENSMUSG00000048756.
ENSMUST00000105502; ENSMUSP00000101141; ENSMUSG00000048756.
ENSMUST00000175881; ENSMUSP00000135380; ENSMUSG00000048756.
GeneIDi56484.
KEGGimmu:56484.
UCSCiuc007eyl.1. mouse.

Organism-specific databases

CTDi2309.
MGIiMGI:1890081. Foxo3.

Phylogenomic databases

eggNOGiCOG5025.
GeneTreeiENSGT00790000123003.
HOGENOMiHOG000169927.
HOVERGENiHBG078744.
InParanoidiQ9WVH4.
KOiK09408.
OMAiWMINPDG.
OrthoDBiEOG7R2BJD.
PhylomeDBiQ9WVH4.
TreeFamiTF315583.

Enzyme and pathway databases

ReactomeiREACT_308448. AKT phosphorylates targets in the nucleus.
REACT_331083. Signaling by NODAL.

Miscellaneous databases

ChiTaRSiFoxo3. mouse.
NextBioi312750.
PROiQ9WVH4.
SOURCEiSearch...

Gene expression databases

BgeeiQ9WVH4.
ExpressionAtlasiQ9WVH4. baseline and differential.
GenevisibleiQ9WVH4. MM.

Family and domain databases

Gene3Di1.10.10.10. 1 hit.
InterProiIPR001766. TF_fork_head.
IPR011991. WHTH_DNA-bd_dom.
[Graphical view]
PfamiPF00250. Fork_head. 1 hit.
[Graphical view]
PRINTSiPR00053. FORKHEAD.
SMARTiSM00339. FH. 1 hit.
[Graphical view]
PROSITEiPS00658. FORK_HEAD_2. 1 hit.
PS50039. FORK_HEAD_3. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Identification and characterization of members of the FKHR (FOX O) subclass of winged-helix transcription factors in the mouse."
    Biggs W.H. III, Cavenee W.K., Arden K.C.
    Mamm. Genome 12:416-425(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
  2. "The transcriptional landscape of the mammalian genome."
    Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.
    , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
    Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Strain: C57BL/6J.
    Tissue: Cerebellum.
  3. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    Strain: C57BL/6J.
  4. Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.
    Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  5. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-255.
  6. "SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restriction."
    Wang F., Nguyen M., Qin F.X., Tong Q.
    Aging Cell 6:505-514(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: ACETYLATION, DEACETYLATION BY SIRT2, INTERACTION WITH SIRT2.
  7. "Novel repressor regulates insulin sensitivity through interaction with Foxo1."
    Nakae J., Cao Y., Hakuno F., Takemori H., Kawano Y., Sekioka R., Abe T., Kiyonari H., Tanaka T., Sakai J., Takahashi S., Itoh H.
    EMBO J. 31:2275-2295(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: TISSUE SPECIFICITY.
  8. "SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways."
    Park J., Chen Y., Tishkoff D.X., Peng C., Tan M., Dai L., Xie Z., Zhang Y., Zwaans B.M., Skinner M.E., Lombard D.B., Zhao Y.
    Mol. Cell 50:919-930(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-241, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Embryonic fibroblast.

Entry informationi

Entry nameiFOXO3_MOUSE
AccessioniPrimary (citable) accession number: Q9WVH4
Secondary accession number(s): D3Z6Y6, Q05CZ4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: January 25, 2012
Last sequence update: November 1, 1999
Last modified: July 22, 2015
This is version 136 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

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 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.