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Protein

Mitogen-activated protein kinase 12

Gene

MAPK12

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

Functioni

Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK12 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors such as ELK1 and ATF2. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases such as MAPKAPK2, which are activated through phosphorylation and further phosphorylate additional targets. Plays a role in myoblast differentiation and also in the down-regulation of cyclin D1 in response to hypoxia in adrenal cells suggesting MAPK12 may inhibit cell proliferation while promoting differentiation. Phosphorylates DLG1. Following osmotic shock, MAPK12 in the cell nucleus increases its association with nuclear DLG1, thereby causing dissociation of DLG1-SFPQ complexes. This function is independent of its catalytic activity and could affect mRNA processing and/or gene transcription to aid cell adaptation to osmolarity changes in the environment. Regulates UV-induced checkpoint signaling and repair of UV-induced DNA damage and G2 arrest after gamma-radiation exposure. MAPK12 is involved in the regulation of SLC2A1 expression and basal glucose uptake in L6 myotubes; and negatively regulates SLC2A4 expression and contraction-mediated glucose uptake in adult skeletal muscle. C-Jun (JUN) phosphorylation is stimulated by MAPK14 and inhibited by MAPK12, leading to a distinct AP-1 regulation. MAPK12 is required for the normal kinetochore localization of PLK1, prevents chromosomal instability and supports mitotic cell viability. MAPK12-signaling is also positively regulating the expansion of transient amplifying myogenic precursor cells during muscle growth and regeneration.7 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.1 Publication

Cofactori

Mg2+1 PublicationNote: Binds 2 magnesium ions.1 Publication

Enzyme regulationi

Activated by phosphorylation on threonine and tyrosine. MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the activation of MAPK12 induced by environmental stress, whereas MAP2K6/MKK6 is the major MAPK12 activator in response to TNF-alpha.2 Publications

Kineticsi

  1. KM=37 µM for ATP1 Publication
  2. KM=313 µM for EGFR substrate peptide1 Publication
  3. KM=254 µM for GST-ATF21 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Binding sitei56ATPPROSITE-ProRule annotation1
    Active sitei153Proton acceptorPROSITE-ProRule annotation1

    Regions

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Nucleotide bindingi33 – 41ATPPROSITE-ProRule annotation9

    GO - Molecular functioni

    • ATP binding Source: UniProtKB-KW
    • magnesium ion binding Source: UniProtKB
    • MAP kinase activity Source: ProtInc
    • protein serine/threonine kinase activity Source: UniProtKB

    GO - Biological processi

    • cell cycle arrest Source: ProtInc
    • DNA damage induced protein phosphorylation Source: ProtInc
    • muscle organ development Source: ProtInc
    • myoblast differentiation Source: UniProtKB
    • peptidyl-serine phosphorylation Source: BHF-UCL
    • positive regulation of muscle cell differentiation Source: Reactome
    • positive regulation of peptidase activity Source: ParkinsonsUK-UCL
    • regulation of transcription, DNA-templated Source: UniProtKB-KW
    • signal transduction Source: ProtInc
    • transcription, DNA-templated Source: UniProtKB-KW
    • vascular endothelial growth factor receptor signaling pathway Source: Reactome
    Complete GO annotation...

    Keywords - Molecular functioni

    Kinase, Serine/threonine-protein kinase, Transferase

    Keywords - Biological processi

    Cell cycle, Stress response, Transcription, Transcription regulation

    Keywords - Ligandi

    ATP-binding, Magnesium, Metal-binding, Nucleotide-binding

    Enzyme and pathway databases

    BioCyciZFISH:HS01100-MONOMER.
    BRENDAi2.7.11.24. 2681.
    ReactomeiR-HSA-168638. NOD1/2 Signaling Pathway.
    R-HSA-171007. p38MAPK events.
    R-HSA-2151209. Activation of PPARGC1A (PGC-1alpha) by phosphorylation.
    R-HSA-375170. CDO in myogenesis.
    R-HSA-376172. DSCAM interactions.
    R-HSA-4420097. VEGFA-VEGFR2 Pathway.
    SignaLinkiP53778.
    SIGNORiP53778.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Mitogen-activated protein kinase 12 (EC:2.7.11.241 Publication)
    Short name:
    MAP kinase 12
    Short name:
    MAPK 12
    Alternative name(s):
    Extracellular signal-regulated kinase 6
    Short name:
    ERK-6
    Mitogen-activated protein kinase p38 gamma
    Short name:
    MAP kinase p38 gamma
    Stress-activated protein kinase 3
    Gene namesi
    Name:MAPK12
    Synonyms:ERK6, SAPK3
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 22

    Organism-specific databases

    HGNCiHGNC:6874. MAPK12.

    Subcellular locationi

    • Cytoplasm
    • Nucleus
    • Mitochondrion

    • Note: Mitochondrial when associated with SH3BP5. In skeletal muscle colocalizes with SNTA1 at the neuromuscular junction and throughout the sarcolemma (By similarity).By similarity

    GO - Cellular componenti

    Complete GO annotation...

    Keywords - Cellular componenti

    Cytoplasm, Mitochondrion, Nucleus

    Pathology & Biotechi

    Involvement in diseasei

    MAPK is overexpressed in highly metastatic breast cancer cell lines and its expression is preferentially associated with basal-like and metastatic phenotypes of breast tumor samples.

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi179D → A: Emulation of the active state. 1 Publication1
    Mutagenesisi185Y → F: Loss of activity. 1 Publication1
    Mutagenesisi330F → S: No effect. 1 Publication1

    Organism-specific databases

    DisGeNETi6300.
    OpenTargetsiENSG00000188130.
    PharmGKBiPA30619.

    Chemistry databases

    ChEMBLiCHEMBL4674.
    GuidetoPHARMACOLOGYi1501.

    Polymorphism and mutation databases

    BioMutaiMAPK12.
    DMDMi2851522.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00001862821 – 367Mitogen-activated protein kinase 12Add BLAST367

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei183Phosphothreonine; by MAP2K3 and MAP2K6By similarity1
    Modified residuei185PhosphotyrosineCombined sources1

    Post-translational modificationi

    Dually phosphorylated on Thr-183 and Tyr-185 by MAP2K3/MKK3 and MAP2K6/MKK6, which activates the enzyme.2 Publications
    Ubiquitinated. Ubiquitination leads to degradation by the proteasome pathway.1 Publication

    Keywords - PTMi

    Phosphoprotein, Ubl conjugation

    Proteomic databases

    EPDiP53778.
    MaxQBiP53778.
    PaxDbiP53778.
    PeptideAtlasiP53778.
    PRIDEiP53778.

    PTM databases

    iPTMnetiP53778.
    PhosphoSitePlusiP53778.

    Expressioni

    Tissue specificityi

    Highly expressed in skeletal muscle and heart.2 Publications

    Inductioni

    Expression of MAPK12 is down-regulation by MAPK14 activation.1 Publication

    Gene expression databases

    BgeeiENSG00000188130.
    CleanExiHS_MAPK12.
    ExpressionAtlasiP53778. baseline and differential.
    GenevisibleiP53778. HS.

    Organism-specific databases

    HPAiCAB025483.
    HPA054562.

    Interactioni

    Subunit structurei

    Monomer. Interacts with the PDZ domain of the syntrophin SNTA1. Interacts with SH3BP5. Interacts with LIN7C, SCRIB and SYNJ2BP (By similarity).By similarity

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    PKN1Q165122EBI-602406,EBI-602382
    PTPN4P290742EBI-602406,EBI-710431
    SIAH1Q8IUQ43EBI-602406,EBI-747107

    Protein-protein interaction databases

    BioGridi112207. 24 interactors.
    DIPiDIP-34241N.
    IntActiP53778. 13 interactors.
    MINTiMINT-90266.
    STRINGi9606.ENSP00000215659.

    Chemistry databases

    BindingDBiP53778.

    Structurei

    Secondary structure

    1367
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Beta strandi17 – 21Combined sources5
    Beta strandi24 – 32Combined sources9
    Beta strandi41 – 46Combined sources6
    Turni47 – 49Combined sources3
    Beta strandi52 – 57Combined sources6
    Helixi65 – 80Combined sources16
    Beta strandi90 – 93Combined sources4
    Turni99 – 101Combined sources3
    Beta strandi106 – 110Combined sources5
    Beta strandi113 – 115Combined sources3
    Helixi116 – 122Combined sources7
    Helixi127 – 146Combined sources20
    Helixi156 – 158Combined sources3
    Beta strandi159 – 161Combined sources3
    Beta strandi167 – 169Combined sources3
    Helixi189 – 191Combined sources3
    Helixi195 – 198Combined sources4
    Turni199 – 201Combined sources3
    Helixi207 – 221Combined sources15
    Helixi231 – 242Combined sources12
    Helixi247 – 251Combined sources5
    Helixi256 – 264Combined sources9
    Helixi273 – 275Combined sources3
    Helixi282 – 291Combined sources10
    Turni296 – 298Combined sources3
    Helixi302 – 307Combined sources6
    Helixi309 – 311Combined sources3
    Turni312 – 314Combined sources3
    Helixi337 – 349Combined sources13

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    1CM8X-ray2.40A/B1-367[»]
    4QUMX-ray2.52B182-190[»]
    ProteinModelPortaliP53778.
    SMRiP53778.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP53778.

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini27 – 311Protein kinasePROSITE-ProRule annotationAdd BLAST285

    Motif

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Motifi183 – 185TXY3

    Domaini

    The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.

    Sequence similaritiesi

    Contains 1 protein kinase domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiKOG0660. Eukaryota.
    ENOG410XNY0. LUCA.
    GeneTreeiENSGT00550000074271.
    HOGENOMiHOG000233024.
    HOVERGENiHBG014652.
    InParanoidiP53778.
    KOiK04441.
    OMAiMKHEKLG.
    OrthoDBiEOG091G08QL.
    PhylomeDBiP53778.
    TreeFamiTF105100.

    Family and domain databases

    InterProiIPR011009. Kinase-like_dom.
    IPR003527. MAP_kinase_CS.
    IPR008352. MAPK_p38.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    [Graphical view]
    PfamiPF00069. Pkinase. 1 hit.
    [Graphical view]
    PRINTSiPR01773. P38MAPKINASE.
    SMARTiSM00220. S_TKc. 1 hit.
    [Graphical view]
    SUPFAMiSSF56112. SSF56112. 1 hit.
    PROSITEiPS01351. MAPK. 1 hit.
    PS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    [Graphical view]

    Sequences (2)i

    Sequence statusi: Complete.

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

    Isoform 1 (identifier: P53778-1) [UniParc]FASTAAdd to basket

    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
    MSSPPPARSG FYRQEVTKTA WEVRAVYRDL QPVGSGAYGA VCSAVDGRTG
    60 70 80 90 100
    AKVAIKKLYR PFQSELFAKR AYRELRLLKH MRHENVIGLL DVFTPDETLD
    110 120 130 140 150
    DFTDFYLVMP FMGTDLGKLM KHEKLGEDRI QFLVYQMLKG LRYIHAAGII
    160 170 180 190 200
    HRDLKPGNLA VNEDCELKIL DFGLARQADS EMTGYVVTRW YRAPEVILNW
    210 220 230 240 250
    MRYTQTVDIW SVGCIMAEMI TGKTLFKGSD HLDQLKEIMK VTGTPPAEFV
    260 270 280 290 300
    QRLQSDEAKN YMKGLPELEK KDFASILTNA SPLAVNLLEK MLVLDAEQRV
    310 320 330 340 350
    TAGEALAHPY FESLHDTEDE PQVQKYDDSF DDVDRTLDEW KRVTYKEVLS
    360
    FKPPRQLGAR VSKETPL
    Length:367
    Mass (Da):41,940
    Last modified:July 15, 1998 - v3
    Checksum:iEF680401D8E40610
    GO
    Isoform 2 (identifier: P53778-2) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         142-151: Missing.

    Note: No experimental confirmation available.
    Show »
    Length:357
    Mass (Da):40,808
    Checksum:i35F0C4A10EB77B20
    GO

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti7A → T in CAA55984 (PubMed:8633070).Curated1
    Sequence conflicti70R → L in CAA55984 (PubMed:8633070).Curated1
    Sequence conflicti138L → M in CAA55984 (PubMed:8633070).Curated1
    Sequence conflicti201 – 202MR → IA in CAA55984 (PubMed:8633070).Curated2
    Sequence conflicti261Y → N in AAB40118 (PubMed:8920915).Curated1
    Sequence conflicti297 – 298EQ → DI in CAA55984 (PubMed:8633070).Curated2
    Sequence conflicti300V → L in CAA55984 (PubMed:8633070).Curated1
    Sequence conflicti305A → F in CAA55984 (PubMed:8633070).Curated1
    Sequence conflicti307A → S in CAA55984 (PubMed:8633070).Curated1
    Sequence conflicti332 – 333DV → YF in CAA55984 (PubMed:8633070).Curated2

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_042265103T → M.2 PublicationsCorresponds to variant rs34422484dbSNPEnsembl.1
    Natural variantiVAR_042266230D → N.1 PublicationCorresponds to variant rs35396905dbSNPEnsembl.1
    Natural variantiVAR_012002244T → M.Corresponds to variant rs2066776dbSNPEnsembl.1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_055224142 – 151Missing in isoform 2. 1 Publication10

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    X79483 mRNA. Translation: CAA55984.1.
    Y10487 mRNA. Translation: CAA71511.1.
    U66243 mRNA. Translation: AAB40118.1.
    CR456515 mRNA. Translation: CAG30401.1.
    AL022328 Genomic DNA. No translation available.
    BC015741 mRNA. Translation: AAH15741.1.
    CCDSiCCDS14089.1. [P53778-1]
    CCDS77688.1. [P53778-2]
    PIRiJC5252.
    JC6138.
    RefSeqiNP_001290181.1. NM_001303252.1. [P53778-2]
    NP_002960.2. NM_002969.4. [P53778-1]
    UniGeneiHs.432642.

    Genome annotation databases

    EnsembliENST00000215659; ENSP00000215659; ENSG00000188130. [P53778-1]
    ENST00000622558; ENSP00000479972; ENSG00000188130. [P53778-2]
    GeneIDi6300.
    KEGGihsa:6300.
    UCSCiuc003bkl.2. human. [P53778-1]

    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
    X79483 mRNA. Translation: CAA55984.1.
    Y10487 mRNA. Translation: CAA71511.1.
    U66243 mRNA. Translation: AAB40118.1.
    CR456515 mRNA. Translation: CAG30401.1.
    AL022328 Genomic DNA. No translation available.
    BC015741 mRNA. Translation: AAH15741.1.
    CCDSiCCDS14089.1. [P53778-1]
    CCDS77688.1. [P53778-2]
    PIRiJC5252.
    JC6138.
    RefSeqiNP_001290181.1. NM_001303252.1. [P53778-2]
    NP_002960.2. NM_002969.4. [P53778-1]
    UniGeneiHs.432642.

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    1CM8X-ray2.40A/B1-367[»]
    4QUMX-ray2.52B182-190[»]
    ProteinModelPortaliP53778.
    SMRiP53778.
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi112207. 24 interactors.
    DIPiDIP-34241N.
    IntActiP53778. 13 interactors.
    MINTiMINT-90266.
    STRINGi9606.ENSP00000215659.

    Chemistry databases

    BindingDBiP53778.
    ChEMBLiCHEMBL4674.
    GuidetoPHARMACOLOGYi1501.

    PTM databases

    iPTMnetiP53778.
    PhosphoSitePlusiP53778.

    Polymorphism and mutation databases

    BioMutaiMAPK12.
    DMDMi2851522.

    Proteomic databases

    EPDiP53778.
    MaxQBiP53778.
    PaxDbiP53778.
    PeptideAtlasiP53778.
    PRIDEiP53778.

    Protocols and materials databases

    DNASUi6300.
    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENST00000215659; ENSP00000215659; ENSG00000188130. [P53778-1]
    ENST00000622558; ENSP00000479972; ENSG00000188130. [P53778-2]
    GeneIDi6300.
    KEGGihsa:6300.
    UCSCiuc003bkl.2. human. [P53778-1]

    Organism-specific databases

    CTDi6300.
    DisGeNETi6300.
    GeneCardsiMAPK12.
    HGNCiHGNC:6874. MAPK12.
    HPAiCAB025483.
    HPA054562.
    MIMi602399. gene.
    neXtProtiNX_P53778.
    OpenTargetsiENSG00000188130.
    PharmGKBiPA30619.
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiKOG0660. Eukaryota.
    ENOG410XNY0. LUCA.
    GeneTreeiENSGT00550000074271.
    HOGENOMiHOG000233024.
    HOVERGENiHBG014652.
    InParanoidiP53778.
    KOiK04441.
    OMAiMKHEKLG.
    OrthoDBiEOG091G08QL.
    PhylomeDBiP53778.
    TreeFamiTF105100.

    Enzyme and pathway databases

    BioCyciZFISH:HS01100-MONOMER.
    BRENDAi2.7.11.24. 2681.
    ReactomeiR-HSA-168638. NOD1/2 Signaling Pathway.
    R-HSA-171007. p38MAPK events.
    R-HSA-2151209. Activation of PPARGC1A (PGC-1alpha) by phosphorylation.
    R-HSA-375170. CDO in myogenesis.
    R-HSA-376172. DSCAM interactions.
    R-HSA-4420097. VEGFA-VEGFR2 Pathway.
    SignaLinkiP53778.
    SIGNORiP53778.

    Miscellaneous databases

    EvolutionaryTraceiP53778.
    GeneWikiiMAPK12.
    GenomeRNAii6300.
    PROiP53778.
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSG00000188130.
    CleanExiHS_MAPK12.
    ExpressionAtlasiP53778. baseline and differential.
    GenevisibleiP53778. HS.

    Family and domain databases

    InterProiIPR011009. Kinase-like_dom.
    IPR003527. MAP_kinase_CS.
    IPR008352. MAPK_p38.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    [Graphical view]
    PfamiPF00069. Pkinase. 1 hit.
    [Graphical view]
    PRINTSiPR01773. P38MAPKINASE.
    SMARTiSM00220. S_TKc. 1 hit.
    [Graphical view]
    SUPFAMiSSF56112. SSF56112. 1 hit.
    PROSITEiPS01351. MAPK. 1 hit.
    PS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    [Graphical view]
    ProtoNetiSearch...

    Entry informationi

    Entry nameiMK12_HUMAN
    AccessioniPrimary (citable) accession number: P53778
    Secondary accession number(s): Q14260
    , Q6IC53, Q99588, Q99672
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: October 1, 1996
    Last sequence update: July 15, 1998
    Last modified: November 2, 2016
    This is version 184 of the entry and version 3 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 22
      Human chromosome 22: 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. Human and mouse protein kinases
      Human and mouse protein kinases: classification and index
    7. 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.