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Protein

Sestrin-2

Gene

SESN2

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

Functioni

Functions as an intracellular leucine sensor that negatively regulates the TORC1 signaling pathway through the GATOR complex. In absence of leucine, binds the GATOR subcomplex GATOR2 and prevents TORC1 signaling (PubMed:18692468, PubMed:25263562, PubMed:25457612, PubMed:26449471, PubMed:26612684, PubMed:26586190). Binding of leucine to SESN2 disrupts its interaction with GATOR2 thereby activating the TORC1 signaling pathway (PubMed:26449471, PubMed:26586190). This stress-inducible metabolic regulator also plays a role in protection against oxidative and genotoxic stresses. May negatively regulate protein translation in response to endoplasmic reticulum stress, via TORC1 (PubMed:24947615). May positively regulate the transcription by NFE2L2 of genes involved in the response to oxidative stress by facilitating the SQSTM1-mediated autophagic degradation of KEAP1 (PubMed:23274085). May also mediate TP53 inhibition of TORC1 signaling upon genotoxic stress (PubMed:18692468). Has an alkylhydroperoxide reductase activity born by the N-terminal domain of the protein (PubMed:26612684). Was originally reported to contribute to oxidative stress resistance by reducing PRDX1 (PubMed:15105503). However, this could not be confirmed (PubMed:19113821).10 Publications

Catalytic activityi

2 R'-SH + ROOH = R'-S-S-R' + H2O + ROH.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei125Cysteine sulfenic acid (-SOH) intermediate1 Publication1
Binding sitei386Leucine; via carbonyl oxygenCombined sources1 Publication1
Binding sitei451LeucineCombined sources1 Publication1

GO - Molecular functioni

  • GDP-dissociation inhibitor activity Source: Ensembl
  • leucine binding Source: UniProtKB
  • oxidoreductase activity, acting on peroxide as acceptor Source: UniProtKB
  • sulfiredoxin activity Source: UniProtKB

GO - Biological processi

  • autophagy Source: Ensembl
  • cellular oxidant detoxification Source: UniProtKB
  • cellular response to amino acid stimulus Source: UniProtKB
  • cellular response to leucine Source: UniProtKB
  • cellular response to oxidative stress Source: UniProtKB
  • DNA damage response, signal transduction by p53 class mediator Source: UniProtKB
  • fatty acid beta-oxidation Source: Ensembl
  • glucose import Source: Ensembl
  • mitochondrial DNA metabolic process Source: Ensembl
  • negative regulation of cell growth Source: UniProtKB
  • negative regulation of TORC1 signaling Source: UniProtKB
  • negative regulation of translation in response to endoplasmic reticulum stress Source: UniProtKB
  • positive regulation of macroautophagy Source: UniProtKB
  • positive regulation of protein localization to nucleus Source: UniProtKB
  • positive regulation of transcription from RNA polymerase II promoter in response to oxidative stress Source: UniProtKB
  • protein kinase B signaling Source: Ensembl
  • reactive oxygen species metabolic process Source: UniProtKB
  • regulation of cAMP-dependent protein kinase activity Source: Ensembl
  • regulation of gluconeogenesis involved in cellular glucose homeostasis Source: Ensembl
  • regulation of protein phosphorylation Source: UniProtKB
  • regulation of response to reactive oxygen species Source: InterPro
  • response to glucose Source: Ensembl
  • response to insulin Source: Ensembl
  • triglyceride homeostasis Source: Ensembl
Complete GO annotation...

Keywords - Molecular functioni

Oxidoreductase

Enzyme and pathway databases

BioCyciZFISH:ENSG00000130766-MONOMER.
ReactomeiR-HSA-5628897. TP53 Regulates Metabolic Genes.

Names & Taxonomyi

Protein namesi
Recommended name:
Sestrin-2Curated (EC:1.11.1.151 Publication)
Alternative name(s):
Hypoxia-induced gene1 Publication
Gene namesi
Name:SESN2Imported
Synonyms:Hi951 Publication, SEST21 Publication
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

HGNCiHGNC:20746. SESN2.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi86H → A: Loss of leucine-binding. 1 Publication1
Mutagenesisi87P → S: No effect on the ability to inhibit the TORC1 signaling pathway. 1 Publication1
Mutagenesisi113H → E: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with C-128. 1 Publication1
Mutagenesisi125C → S: Decreased alkylhydroperoxide reductase activity and loss of the ability to decrease intracellular reactive oxygen species. No effect on interaction with the GATOR2 complex. No effect on inhibition of TOR signaling. 3 Publications1
Mutagenesisi127Y → F: Decreased alkylhydroperoxide reductase activity. No effect on the ability to inhibit the TORC1 signaling pathway. 1 Publication1
Mutagenesisi128L → C: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with E-113. 1 Publication1
Mutagenesisi132H → A: Decreased alkylhydroperoxide reductase activity. No effect on the ability to inhibit the TORC1 signaling pathway. 1 Publication1
Mutagenesisi190S → W: Loss of interaction with GATOR2. No effect on leucine-binding. Unable to mediate leucine-induced inhibition of the TORC1 signaling pathway. 1 Publication1
Mutagenesisi204C → S: No effect on alkylhydroperoxide reductase activity. No effect on the ability to inhibit the TORC1 signaling pathway. 1 Publication1
Mutagenesisi214C → S: No effect on alkylhydroperoxide reductase activity. 1 Publication1
Mutagenesisi258V → R: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with L-259 and R-261. 1 Publication1
Mutagenesisi259E → L: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with R-258 and R-261. 1 Publication1
Mutagenesisi261L → A: Decreased leucine-binding. 1 Publication1
Mutagenesisi261L → R: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with R-258 and L-259. 1 Publication1
Mutagenesisi262 – 264MER → LMM: No effect on the ability to inhibit the TORC1 signaling pathway. 1 Publication3
Mutagenesisi264R → P: No effect on the ability to inhibit the TORC1 signaling pathway. 1 Publication1
Mutagenesisi314C → S: No effect on ability to decrease intracellular reactive oxygen species. 1 Publication1
Mutagenesisi336 – 337TF → AA: No effect on the ability to inhibit the TORC1 signaling pathway. 1 Publication2
Mutagenesisi340 – 341QD → AA: No effect on the ability to inhibit the TORC1 signaling pathway. 1 Publication2
Mutagenesisi373L → A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-376. 1 Publication1
Mutagenesisi374T → A: Loss of leucine-binding. Constituvely interacts with the GATOR2 complex. 1 Publication1
Mutagenesisi375Y → A: Loss of leucine-binding. 1 Publication1
Mutagenesisi376N → A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-373. 1 Publication1
Mutagenesisi385D → A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-387. 1 Publication1
Mutagenesisi386T → A: Loss of leucine-binding. Constituvely interacts with the GATOR2 complex. 1 Publication1
Mutagenesisi387S → A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-385. 1 Publication1
Mutagenesisi390R → A: Loss of leucine-binding. Constituvely interacts with the GATOR2 complex. 1 Publication1
Mutagenesisi399C → S: No effect on alkylhydroperoxide reductase activity. Altered ability to decrease intracellular reactive oxygen species. No effect on the ability to inhibit the TORC1 signaling pathway. 2 Publications1
Mutagenesisi406 – 407DD → AA: Loss of interaction with the GATOR2 complex. No effect on leucine-binding. 1 Publication2
Mutagenesisi406D → A: No effect on alkylhydroperoxide reductase activity. Loss of interaction with the GATOR2 complex. Unable to inhibit the TORC1 signaling pathway. 1 Publication1
Mutagenesisi407D → A: No effect on alkylhydroperoxide reductase activity. Loss of interaction with the GATOR2 complex. Unable to inhibit the TORC1 signaling pathway. 1 Publication1
Mutagenesisi409D → A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-411 and A-415. 1 Publication1
Mutagenesisi411G → A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-409 and A-415. 1 Publication1
Mutagenesisi415Q → A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-409 and A-411. 1 Publication1
Mutagenesisi419R → A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-422 and A-426. 1 Publication1
Mutagenesisi422K → A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-419 and A-426. 1 Publication1
Mutagenesisi426K → A: No effect on the ability to inhibit the TORC1 signaling pathway; when associated with A-419 and A-422. 1 Publication1
Mutagenesisi430C → S: No effect on alkylhydroperoxide reductase activity. Altered ability to decrease intracellular reactive oxygen species. No effect on the ability to inhibit the TORC1 signaling pathway. 2 Publications1
Mutagenesisi444W → E: Loss of leucine-binding. 1 Publication1
Mutagenesisi444W → L: Decreased affinity for leucine. Requires increased leucine concentration to dissociate from GATOR2 and activate TORC1 signaling. 1 Publication1
Mutagenesisi451E → A: Decreased leucine-binding. 1 Publication1
Mutagenesisi451E → Q: Loss of leucine-binding. Constituvely interacts with the GATOR2 complex. 1 Publication1

Organism-specific databases

DisGeNETi83667.
OpenTargetsiENSG00000130766.
PharmGKBiPA134882791.

Polymorphism and mutation databases

BioMutaiSESN2.
DMDMi13633882.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002211811 – 480Sestrin-2Add BLAST480

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei1N-acetylmethionineCombined sources1
Modified residuei249PhosphoserineCombined sources1

Post-translational modificationi

Phosphorylated by ULK1 at multiple sites.1 Publication

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiP58004.
MaxQBiP58004.
PaxDbiP58004.
PeptideAtlasiP58004.
PRIDEiP58004.

PTM databases

iPTMnetiP58004.
PhosphoSitePlusiP58004.

Expressioni

Tissue specificityi

Widely expressed.1 Publication

Inductioni

Up-regulated by hypoxia and DNA damage (PubMed:12203114). Up-regulated by treatments inducing endoplasmic reticulum stress (PubMed:24947615).2 Publications

Gene expression databases

BgeeiENSG00000130766.
CleanExiHS_SESN2.
GenevisibleiP58004. HS.

Organism-specific databases

HPAiHPA018191.

Interactioni

Subunit structurei

Interacts with the GATOR2 complex which is composed of MIOS, SEC13, SEH1L, WDR24 and WDR59; the interaction is negatively regulated by leucine (PubMed:25263562, PubMed:25457612, PubMed:26449471). Interacts with RRAGA, RRAGB, RRAGC and RRAGD; may function as a guanine nucleotide dissociation inhibitor for RRAGs and regulate them (PubMed:25259925). May interact with the TORC2 complex (By similarity). Interacts with KEAP1, RBX1, SQSTM and ULK1; to regulate the degradation of KEAP1 (PubMed:23274085, PubMed:25040165). May also associate with the complex composed of TSC1, TSC2 and the AMP-responsive protein kinase/AMPK to regulate TORC1 signaling (PubMed:18692468). May interact with PRDX1 (PubMed:15105503).By similarity8 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
SQSTM1Q135015EBI-3939642,EBI-307104
Ulk1O704055EBI-3939642,EBI-8390771From a different organism.

Protein-protein interaction databases

BioGridi123724. 12 interactors.
DIPiDIP-62044N.
IntActiP58004. 8 interactors.
MINTiMINT-4715291.
STRINGi9606.ENSP00000253063.

Structurei

Secondary structure

1480
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi68 – 71Combined sources4
Turni72 – 74Combined sources3
Helixi78 – 83Combined sources6
Helixi87 – 102Combined sources16
Helixi109 – 121Combined sources13
Turni122 – 124Combined sources3
Helixi126 – 138Combined sources13
Helixi143 – 147Combined sources5
Helixi149 – 151Combined sources3
Helixi154 – 157Combined sources4
Helixi160 – 168Combined sources9
Helixi170 – 172Combined sources3
Helixi175 – 182Combined sources8
Beta strandi185 – 187Combined sources3
Helixi191 – 213Combined sources23
Beta strandi228 – 230Combined sources3
Beta strandi235 – 237Combined sources3
Helixi257 – 270Combined sources14
Helixi283 – 292Combined sources10
Helixi313 – 315Combined sources3
Beta strandi328 – 330Combined sources3
Helixi339 – 341Combined sources3
Turni344 – 347Combined sources4
Helixi348 – 355Combined sources8
Helixi357 – 371Combined sources15
Beta strandi378 – 380Combined sources3
Helixi387 – 400Combined sources14
Helixi411 – 416Combined sources6
Helixi419 – 430Combined sources12
Helixi432 – 434Combined sources3
Helixi437 – 442Combined sources6
Helixi449 – 479Combined sources31

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
5CUFX-ray3.50A/B/C/D/E1-480[»]
5DJ4X-ray2.70A/B/C/D/E1-480[»]
5T0NX-ray3.00A/B/C/D/E1-480[»]
ProteinModelPortaliP58004.
SMRiP58004.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni66 – 239N-terminal domain; mediates the alkylhydroperoxide reductase activity1 PublicationAdd BLAST174
Regioni308 – 480C-terminal domain; mediates TORC1 regulation1 PublicationAdd BLAST173
Regioni374 – 377Leucine-bindingCombined sources1 Publication4

Domaini

Composed of an N-terminal domain that has an alkylhydroperoxide reductase activity and a C-terminal domain that mediates interaction with GATOR2 through which it regulates TORC1 signaling.1 Publication

Sequence similaritiesi

Belongs to the sestrin family.Curated

Phylogenomic databases

eggNOGiKOG3746. Eukaryota.
ENOG410XP7Z. LUCA.
GeneTreeiENSGT00440000040103.
HOGENOMiHOG000232949.
HOVERGENiHBG054648.
InParanoidiP58004.
KOiK20394.
OMAiASSWRHY.
OrthoDBiEOG091G0IVA.
PhylomeDBiP58004.
TreeFamiTF314230.

Family and domain databases

Gene3Di1.20.1290.10. 1 hit.
InterProiIPR029032. AhpD-like.
IPR006730. Sestrin.
[Graphical view]
PfamiPF04636. PA26. 1 hit.
[Graphical view]
SUPFAMiSSF69118. SSF69118. 1 hit.

Sequencei

Sequence statusi: Complete.

P58004-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MIVADSECRA ELKDYLRFAP GGVGDSGPGE EQRESRARRG PRGPSAFIPV
60 70 80 90 100
EEVLREGAES LEQHLGLEAL MSSGRVDNLA VVMGLHPDYF TSFWRLHYLL
110 120 130 140 150
LHTDGPLASS WRHYIAIMAA ARHQCSYLVG SHMAEFLQTG GDPEWLLGLH
160 170 180 190 200
RAPEKLRKLS EINKLLAHRP WLITKEHIQA LLKTGEHTWS LAELIQALVL
210 220 230 240 250
LTHCHSLSSF VFGCGILPEG DADGSPAPQA PTPPSEQSSP PSRDPLNNSG
260 270 280 290 300
GFESARDVEA LMERMQQLQE SLLRDEGTSQ EEMESRFELE KSESLLVTPS
310 320 330 340 350
ADILEPSPHP DMLCFVEDPT FGYEDFTRRG AQAPPTFRAQ DYTWEDHGYS
360 370 380 390 400
LIQRLYPEGG QLLDEKFQAA YSLTYNTIAM HSGVDTSVLR RAIWNYIHCV
410 420 430 440 450
FGIRYDDYDY GEVNQLLERN LKVYIKTVAC YPEKTTRRMY NLFWRHFRHS
460 470 480
EKVHVNLLLL EARMQAALLY ALRAITRYMT
Length:480
Mass (Da):54,494
Last modified:April 27, 2001 - v1
Checksum:i9C13371316D84060
GO

Sequence cautioni

The sequence BAB55438 differs from that shown. Reason: Erroneous initiation.Curated

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_022101320T → A.Corresponds to variant rs2274848dbSNPEnsembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY123223 mRNA. Translation: AAM92261.1.
AL136551 mRNA. Translation: CAB66486.1.
AK027896 mRNA. Translation: BAB55438.1. Different initiation.
AK025640 mRNA. No translation available.
AK315710 mRNA. Translation: BAG38070.1.
AL353622 Genomic DNA. Translation: CAI19133.1.
CH471059 Genomic DNA. Translation: EAX07703.1.
BC013304 mRNA. Translation: AAH13304.1.
BC033719 mRNA. Translation: AAH33719.1.
CCDSiCCDS321.1.
RefSeqiNP_113647.1. NM_031459.4.
UniGeneiHs.469543.

Genome annotation databases

EnsembliENST00000253063; ENSP00000253063; ENSG00000130766.
GeneIDi83667.
KEGGihsa:83667.
UCSCiuc001bps.4. human.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY123223 mRNA. Translation: AAM92261.1.
AL136551 mRNA. Translation: CAB66486.1.
AK027896 mRNA. Translation: BAB55438.1. Different initiation.
AK025640 mRNA. No translation available.
AK315710 mRNA. Translation: BAG38070.1.
AL353622 Genomic DNA. Translation: CAI19133.1.
CH471059 Genomic DNA. Translation: EAX07703.1.
BC013304 mRNA. Translation: AAH13304.1.
BC033719 mRNA. Translation: AAH33719.1.
CCDSiCCDS321.1.
RefSeqiNP_113647.1. NM_031459.4.
UniGeneiHs.469543.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
5CUFX-ray3.50A/B/C/D/E1-480[»]
5DJ4X-ray2.70A/B/C/D/E1-480[»]
5T0NX-ray3.00A/B/C/D/E1-480[»]
ProteinModelPortaliP58004.
SMRiP58004.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi123724. 12 interactors.
DIPiDIP-62044N.
IntActiP58004. 8 interactors.
MINTiMINT-4715291.
STRINGi9606.ENSP00000253063.

PTM databases

iPTMnetiP58004.
PhosphoSitePlusiP58004.

Polymorphism and mutation databases

BioMutaiSESN2.
DMDMi13633882.

Proteomic databases

EPDiP58004.
MaxQBiP58004.
PaxDbiP58004.
PeptideAtlasiP58004.
PRIDEiP58004.

Protocols and materials databases

DNASUi83667.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000253063; ENSP00000253063; ENSG00000130766.
GeneIDi83667.
KEGGihsa:83667.
UCSCiuc001bps.4. human.

Organism-specific databases

CTDi83667.
DisGeNETi83667.
GeneCardsiSESN2.
HGNCiHGNC:20746. SESN2.
HPAiHPA018191.
MIMi607767. gene.
neXtProtiNX_P58004.
OpenTargetsiENSG00000130766.
PharmGKBiPA134882791.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG3746. Eukaryota.
ENOG410XP7Z. LUCA.
GeneTreeiENSGT00440000040103.
HOGENOMiHOG000232949.
HOVERGENiHBG054648.
InParanoidiP58004.
KOiK20394.
OMAiASSWRHY.
OrthoDBiEOG091G0IVA.
PhylomeDBiP58004.
TreeFamiTF314230.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000130766-MONOMER.
ReactomeiR-HSA-5628897. TP53 Regulates Metabolic Genes.

Miscellaneous databases

ChiTaRSiSESN2. human.
GeneWikiiSESN2.
GenomeRNAii83667.
PROiP58004.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000130766.
CleanExiHS_SESN2.
GenevisibleiP58004. HS.

Family and domain databases

Gene3Di1.20.1290.10. 1 hit.
InterProiIPR029032. AhpD-like.
IPR006730. Sestrin.
[Graphical view]
PfamiPF04636. PA26. 1 hit.
[Graphical view]
SUPFAMiSSF69118. SSF69118. 1 hit.
ProtoNetiSearch...

Entry informationi

Entry nameiSESN2_HUMAN
AccessioniPrimary (citable) accession number: P58004
Secondary accession number(s): Q5T7D0, Q96SI5
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 27, 2001
Last sequence update: April 27, 2001
Last modified: November 30, 2016
This is version 135 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 1
    Human chromosome 1: 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.