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Protein

Proton-coupled folate transporter

Gene

SLC46A1

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

Functioni

Has been shown to act both as an intestinal proton-coupled high-affinity folate transporter and as an intestinal heme transporter which mediates heme uptake from the gut lumen into duodenal epithelial cells. The iron is then released from heme and may be transported into the bloodstream. Dietary heme iron is an important nutritional source of iron. Shows a higher affinity for folate than heme.4 Publications

Kineticsi

  1. KM=1.3 µM for folic acid (at pH 5.5)2 Publications
  2. KM=1.5 µM for folic acid (at pH 6.0)2 Publications
  3. KM=2.7 µM for folic acid (at pH 6.5)2 Publications
  4. KM=6.0 µM for folic acid (at pH 7.0)2 Publications
  5. KM=56.2 µM for folic acid (at pH 7.5)2 Publications

    pH dependencei

    Optimum pH is 4.0-5.5. Activity decreases above pH 5.5 and reaches negligible levels at neutral pH and above.2 Publications

    GO - Molecular functioni

    • folic acid binding Source: UniProtKB-KW
    • folic acid transporter activity Source: UniProtKB
    • heme transporter activity Source: Reactome
    • hydrogen ion transmembrane transporter activity Source: BHF-UCL
    • methotrexate transporter activity Source: BHF-UCL

    GO - Biological processi

    • cellular iron ion homeostasis Source: Reactome
    • folic acid import into cell Source: BHF-UCL
    • folic acid metabolic process Source: Reactome
    • folic acid transport Source: UniProtKB
    • hydrogen ion transmembrane transport Source: BHF-UCL
    • intestinal folate absorption Source: BHF-UCL
    • methotrexate transport Source: BHF-UCL
    Complete GO annotation...

    Keywords - Biological processi

    Transport

    Keywords - Ligandi

    Folate-binding

    Enzyme and pathway databases

    ReactomeiR-HSA-196757. Metabolism of folate and pterines.
    R-HSA-917937. Iron uptake and transport.

    Protein family/group databases

    TCDBi2.A.1.50.1. the major facilitator superfamily (mfs).

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Proton-coupled folate transporter
    Alternative name(s):
    G21
    Heme carrier protein 1
    PCFT/HCP1
    Solute carrier family 46 member 1
    Gene namesi
    Name:SLC46A1
    Synonyms:HCP1, PCFT
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 17

    Organism-specific databases

    HGNCiHGNC:30521. SLC46A1.

    Subcellular locationi

    Topology

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Topological domaini1 – 2424CytoplasmicSequence analysisAdd
    BLAST
    Transmembranei25 – 4824HelicalSequence analysisAdd
    BLAST
    Topological domaini49 – 8436ExtracellularSequence analysisAdd
    BLAST
    Transmembranei85 – 10723HelicalSequence analysisAdd
    BLAST
    Topological domaini108 – 1136CytoplasmicSequence analysis
    Transmembranei114 – 13724HelicalSequence analysisAdd
    BLAST
    Topological domaini138 – 1458ExtracellularSequence analysis
    Transmembranei146 – 16823HelicalSequence analysisAdd
    BLAST
    Topological domaini169 – 18012CytoplasmicSequence analysisAdd
    BLAST
    Transmembranei181 – 20323HelicalSequence analysisAdd
    BLAST
    Topological domaini204 – 2129ExtracellularSequence analysis
    Transmembranei213 – 23624HelicalSequence analysisAdd
    BLAST
    Topological domaini237 – 26529CytoplasmicSequence analysisAdd
    BLAST
    Transmembranei266 – 28823HelicalSequence analysisAdd
    BLAST
    Topological domaini289 – 30921ExtracellularSequence analysisAdd
    BLAST
    Transmembranei310 – 32819HelicalSequence analysisAdd
    BLAST
    Topological domaini329 – 3313CytoplasmicSequence analysis
    Transmembranei332 – 35625HelicalSequence analysisAdd
    BLAST
    Topological domaini357 – 3593ExtracellularSequence analysis
    Transmembranei360 – 38122HelicalSequence analysisAdd
    BLAST
    Topological domaini382 – 39312CytoplasmicSequence analysisAdd
    BLAST
    Transmembranei394 – 41219HelicalSequence analysisAdd
    BLAST
    Topological domaini413 – 42412ExtracellularSequence analysisAdd
    BLAST
    Transmembranei425 – 44925HelicalSequence analysisAdd
    BLAST
    Topological domaini450 – 45910CytoplasmicSequence analysis

    GO - Cellular componenti

    • apical plasma membrane Source: UniProtKB
    • brush border membrane Source: Ensembl
    • cell surface Source: UniProtKB
    • cytoplasm Source: UniProtKB
    • integral component of membrane Source: UniProtKB-KW
    • plasma membrane Source: BHF-UCL
    Complete GO annotation...

    Keywords - Cellular componenti

    Cell membrane, Cytoplasm, Membrane

    Pathology & Biotechi

    Involvement in diseasei

    Hereditary folate malabsorption (HFM)6 Publications
    The disease is caused by mutations affecting the gene represented in this entry.
    Disease descriptionRare autosomal recessive disorder characterized by impaired intestinal folate absorption with folate deficiency resulting in anemia, hypoimmunoglobulinemia with recurrent infections, and recurrent or chronic diarrhea. In many patients, neurological abnormalities such as seizures or mental retardation become apparent during early childhood, attributed to impaired transport of folates into the central nervous system. When diagnosed early, the disorder can be treated by administration of folate. If untreated, it can be fatal and, if treatment is delayed, the neurological defects can become permanent.
    See also OMIM:229050
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti113 – 1131R → C in HFM; loss-of-function mutation; targeted to the plasma membrane but has significantly impaired folate transport activity. 1 Publication
    Corresponds to variant rs80338770 [ dbSNP | Ensembl ].
    VAR_058210
    Natural varianti113 – 1131R → S in HFM; abolishes folate uptake. 1 Publication
    Corresponds to variant rs80338770 [ dbSNP | Ensembl ].
    VAR_032825
    Natural varianti147 – 1471G → R in HFM; reduces folate uptake to 13% of normal levels. 1 Publication
    Corresponds to variant rs80338771 [ dbSNP | Ensembl ].
    VAR_032826
    Natural varianti156 – 1561D → Y in HFM; loss of function measured as methotrexate uptake. 1 Publication
    Corresponds to variant rs281875210 [ dbSNP | Ensembl ].
    VAR_067960
    Natural varianti318 – 3181S → R in HFM; abolishes folate uptake. 1 Publication
    Corresponds to variant rs80338772 [ dbSNP | Ensembl ].
    VAR_032827
    Natural varianti335 – 3351A → D in HFM; loss of function measured as methotrexate uptake. 1 Publication
    Corresponds to variant rs281875208 [ dbSNP | Ensembl ].
    VAR_067961
    Natural varianti338 – 3381G → R in HFM; loss of function measured as methotrexate uptake. 1 Publication
    Corresponds to variant rs281875209 [ dbSNP | Ensembl ].
    VAR_067962
    Natural varianti376 – 3761R → Q in HFM; abolishes folate uptake. 1 Publication
    Corresponds to variant rs281875211 [ dbSNP | Ensembl ].
    VAR_067963
    Natural varianti376 – 3761R → W in HFM; abolishes folate uptake. 1 Publication
    Corresponds to variant rs80338773 [ dbSNP | Ensembl ].
    VAR_032828
    Natural varianti425 – 4251P → R in HFM; reduces folate uptake to 3.5% of normal levels. 1 Publication
    Corresponds to variant rs80338774 [ dbSNP | Ensembl ].
    VAR_032829

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi109 – 1091D → A, G, E, K, N or S: Loss of methotrexate uptake. 1 Publication
    Mutagenesisi156 – 1561D → E: Does not affect methotrexate uptake. 1 Publication
    Mutagenesisi156 – 1561D → F, K, N, V or W: Loss of methotrexate uptake. 1 Publication
    Mutagenesisi156 – 1561D → G: 2-fold reduction of methotrexate uptake. 1 Publication
    Mutagenesisi156 – 1561D → S: 8-fold reduction of methotrexate uptake. 1 Publication
    Mutagenesisi376 – 3761R → A, C, E, H, Q or W: Abolishes folate uptake. 1 Publication

    Keywords - Diseasei

    Disease mutation

    Organism-specific databases

    MalaCardsiSLC46A1.
    MIMi229050. phenotype.
    Orphaneti90045. Hereditary folate malabsorption.
    PharmGKBiPA162403775.

    Chemistry

    ChEMBLiCHEMBL1795188.
    DrugBankiDB00158. Folic Acid.
    DB00563. Methotrexate.
    DB00795. Sulfasalazine.
    GuidetoPHARMACOLOGYi1213.

    Polymorphism and mutation databases

    DMDMi74732636.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 459459Proton-coupled folate transporterPRO_0000084851Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei1 – 11N-acetylmethionineCombined sources
    Modified residuei6 – 61PhosphoserineCombined sources
    Glycosylationi58 – 581N-linked (GlcNAc...)2 Publications
    Glycosylationi68 – 681N-linked (GlcNAc...)1 Publication
    Modified residuei458 – 4581PhosphoserineCombined sources

    Keywords - PTMi

    Acetylation, Glycoprotein, Phosphoprotein

    Proteomic databases

    MaxQBiQ96NT5.
    PaxDbiQ96NT5.
    PeptideAtlasiQ96NT5.
    PRIDEiQ96NT5.

    PTM databases

    iPTMnetiQ96NT5.
    PhosphoSiteiQ96NT5.
    SwissPalmiQ96NT5.

    Expressioni

    Tissue specificityi

    Expressed in kidney, liver, placenta, small intestine, spleen, retina and retinal pigment epithelium. Lower levels found in colon and testis. Very low levels in brain, lung, stomach, heart and muscle. In intestine, expressed in duodenum with lower levels in jejunum, ileum, cecum, rectum and segments of the colon.2 Publications

    Gene expression databases

    BgeeiENSG00000076351.
    CleanExiHS_SLC46A1.
    ExpressionAtlasiQ96NT5. baseline and differential.
    GenevisibleiQ96NT5. HS.

    Organism-specific databases

    HPAiCAB011614.

    Interactioni

    Subunit structurei

    Monomer.1 Publication

    Protein-protein interaction databases

    BioGridi125236. 2 interactions.
    IntActiQ96NT5. 2 interactions.
    STRINGi9606.ENSP00000395653.

    Chemistry

    BindingDBiQ96NT5.

    Structurei

    3D structure databases

    ProteinModelPortaliQ96NT5.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Sequence similaritiesi

    Keywords - Domaini

    Transmembrane, Transmembrane helix

    Phylogenomic databases

    eggNOGiKOG2816. Eukaryota.
    ENOG410ZVCA. LUCA.
    GeneTreeiENSGT00530000063076.
    HOGENOMiHOG000054191.
    HOVERGENiHBG055334.
    InParanoidiQ96NT5.
    KOiK14613.
    OMAiFANTHAQ.
    OrthoDBiEOG091G08MP.
    PhylomeDBiQ96NT5.
    TreeFamiTF315701.

    Family and domain databases

    CDDicd06174. MFS. 1 hit.
    InterProiIPR011701. MFS.
    IPR020846. MFS_dom.
    IPR005829. Sugar_transporter_CS.
    [Graphical view]
    PfamiPF07690. MFS_1. 1 hit.
    [Graphical view]
    SUPFAMiSSF103473. SSF103473. 1 hit.
    PROSITEiPS50850. MFS. 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: Q96NT5-1) [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
    MEGSASPPEK PRARPAAAVL CRGPVEPLVF LANFALVLQG PLTTQYLWHR
    60 70 80 90 100
    FSADLGYNGT RQRGGCSNRS ADPTMQEVET LTSHWTLYMN VGGFLVGLFS
    110 120 130 140 150
    STLLGAWSDS VGRRPLLVLA SLGLLLQALV SVFVVQLQLH VGYFVLGRIL
    160 170 180 190 200
    CALLGDFGGL LAASFASVAD VSSSRSRTFR MALLEASIGV AGMLASLLGG
    210 220 230 240 250
    HWLRAQGYAN PFWLALALLI AMTLYAAFCF GETLKEPKST RLFTFRHHRS
    260 270 280 290 300
    IVQLYVAPAP EKSRKHLALY SLAIFVVITV HFGAQDILTL YELSTPLCWD
    310 320 330 340 350
    SKLIGYGSAA QHLPYLTSLL ALKLLQYCLA DAWVAEIGLA FNILGMVVFA
    360 370 380 390 400
    FATITPLMFT GYGLLFLSLV ITPVIRAKLS KLVRETEQGA LFSAVACVNS
    410 420 430 440 450
    LAMLTASGIF NSLYPATLNF MKGFPFLLGA GLLLIPAVLI GMLEKADPHL

    EFQQFPQSP
    Length:459
    Mass (Da):49,771
    Last modified:December 1, 2001 - v1
    Checksum:i119F89E9E4ACA5F4
    GO
    Isoform 2 (identifier: Q96NT5-2) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         361-388: Missing.

    Note: Inactive isoform which results in impaired folate absorption, giving rise to hereditary folate malabsorption (HFM).
    Show »
    Length:431
    Mass (Da):46,644
    Checksum:iEE81E0C20CF70C00
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti394 – 3941A → G in BAB84987 (PubMed:14702039).Curated

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti113 – 1131R → C in HFM; loss-of-function mutation; targeted to the plasma membrane but has significantly impaired folate transport activity. 1 Publication
    Corresponds to variant rs80338770 [ dbSNP | Ensembl ].
    VAR_058210
    Natural varianti113 – 1131R → S in HFM; abolishes folate uptake. 1 Publication
    Corresponds to variant rs80338770 [ dbSNP | Ensembl ].
    VAR_032825
    Natural varianti147 – 1471G → R in HFM; reduces folate uptake to 13% of normal levels. 1 Publication
    Corresponds to variant rs80338771 [ dbSNP | Ensembl ].
    VAR_032826
    Natural varianti156 – 1561D → Y in HFM; loss of function measured as methotrexate uptake. 1 Publication
    Corresponds to variant rs281875210 [ dbSNP | Ensembl ].
    VAR_067960
    Natural varianti295 – 2951T → A.
    Corresponds to variant rs34552966 [ dbSNP | Ensembl ].
    VAR_050302
    Natural varianti318 – 3181S → R in HFM; abolishes folate uptake. 1 Publication
    Corresponds to variant rs80338772 [ dbSNP | Ensembl ].
    VAR_032827
    Natural varianti335 – 3351A → D in HFM; loss of function measured as methotrexate uptake. 1 Publication
    Corresponds to variant rs281875208 [ dbSNP | Ensembl ].
    VAR_067961
    Natural varianti338 – 3381G → R in HFM; loss of function measured as methotrexate uptake. 1 Publication
    Corresponds to variant rs281875209 [ dbSNP | Ensembl ].
    VAR_067962
    Natural varianti376 – 3761R → Q in HFM; abolishes folate uptake. 1 Publication
    Corresponds to variant rs281875211 [ dbSNP | Ensembl ].
    VAR_067963
    Natural varianti376 – 3761R → W in HFM; abolishes folate uptake. 1 Publication
    Corresponds to variant rs80338773 [ dbSNP | Ensembl ].
    VAR_032828
    Natural varianti425 – 4251P → R in HFM; reduces folate uptake to 3.5% of normal levels. 1 Publication
    Corresponds to variant rs80338774 [ dbSNP | Ensembl ].
    VAR_032829

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei361 – 38828Missing in isoform 2. 2 PublicationsVSP_016053Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AK054669 mRNA. Translation: BAB70789.1.
    AK074161 mRNA. Translation: BAB84987.1.
    DQ496103 Genomic DNA. Translation: ABF47092.1.
    BC010691 mRNA. Translation: AAH10691.1.
    AL832613 mRNA. Translation: CAD89945.1.
    CCDSiCCDS74019.1. [Q96NT5-2]
    CCDS74020.1. [Q96NT5-1]
    RefSeqiNP_001229295.1. NM_001242366.2. [Q96NT5-2]
    NP_542400.2. NM_080669.5. [Q96NT5-1]
    UniGeneiHs.446689.

    Genome annotation databases

    EnsembliENST00000612814; ENSP00000480703; ENSG00000076351. [Q96NT5-1]
    ENST00000618626; ENSP00000483652; ENSG00000076351. [Q96NT5-2]
    GeneIDi113235.
    KEGGihsa:113235.
    UCSCiuc032ezi.2. human. [Q96NT5-1]

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Cross-referencesi

    Web resourcesi

    Mendelian genes solute carrier family 46 (folate transporter), member 1 (SLC46A1)

    Leiden Open Variation Database (LOVD)

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AK054669 mRNA. Translation: BAB70789.1.
    AK074161 mRNA. Translation: BAB84987.1.
    DQ496103 Genomic DNA. Translation: ABF47092.1.
    BC010691 mRNA. Translation: AAH10691.1.
    AL832613 mRNA. Translation: CAD89945.1.
    CCDSiCCDS74019.1. [Q96NT5-2]
    CCDS74020.1. [Q96NT5-1]
    RefSeqiNP_001229295.1. NM_001242366.2. [Q96NT5-2]
    NP_542400.2. NM_080669.5. [Q96NT5-1]
    UniGeneiHs.446689.

    3D structure databases

    ProteinModelPortaliQ96NT5.
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi125236. 2 interactions.
    IntActiQ96NT5. 2 interactions.
    STRINGi9606.ENSP00000395653.

    Chemistry

    BindingDBiQ96NT5.
    ChEMBLiCHEMBL1795188.
    DrugBankiDB00158. Folic Acid.
    DB00563. Methotrexate.
    DB00795. Sulfasalazine.
    GuidetoPHARMACOLOGYi1213.

    Protein family/group databases

    TCDBi2.A.1.50.1. the major facilitator superfamily (mfs).

    PTM databases

    iPTMnetiQ96NT5.
    PhosphoSiteiQ96NT5.
    SwissPalmiQ96NT5.

    Polymorphism and mutation databases

    DMDMi74732636.

    Proteomic databases

    MaxQBiQ96NT5.
    PaxDbiQ96NT5.
    PeptideAtlasiQ96NT5.
    PRIDEiQ96NT5.

    Protocols and materials databases

    DNASUi113235.
    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENST00000612814; ENSP00000480703; ENSG00000076351. [Q96NT5-1]
    ENST00000618626; ENSP00000483652; ENSG00000076351. [Q96NT5-2]
    GeneIDi113235.
    KEGGihsa:113235.
    UCSCiuc032ezi.2. human. [Q96NT5-1]

    Organism-specific databases

    CTDi113235.
    GeneCardsiSLC46A1.
    GeneReviewsiSLC46A1.
    H-InvDBHIX0022189.
    HGNCiHGNC:30521. SLC46A1.
    HPAiCAB011614.
    MalaCardsiSLC46A1.
    MIMi229050. phenotype.
    611672. gene.
    neXtProtiNX_Q96NT5.
    Orphaneti90045. Hereditary folate malabsorption.
    PharmGKBiPA162403775.
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiKOG2816. Eukaryota.
    ENOG410ZVCA. LUCA.
    GeneTreeiENSGT00530000063076.
    HOGENOMiHOG000054191.
    HOVERGENiHBG055334.
    InParanoidiQ96NT5.
    KOiK14613.
    OMAiFANTHAQ.
    OrthoDBiEOG091G08MP.
    PhylomeDBiQ96NT5.
    TreeFamiTF315701.

    Enzyme and pathway databases

    ReactomeiR-HSA-196757. Metabolism of folate and pterines.
    R-HSA-917937. Iron uptake and transport.

    Miscellaneous databases

    GeneWikiiSLC46A1.
    GenomeRNAii113235.
    PROiQ96NT5.
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSG00000076351.
    CleanExiHS_SLC46A1.
    ExpressionAtlasiQ96NT5. baseline and differential.
    GenevisibleiQ96NT5. HS.

    Family and domain databases

    CDDicd06174. MFS. 1 hit.
    InterProiIPR011701. MFS.
    IPR020846. MFS_dom.
    IPR005829. Sugar_transporter_CS.
    [Graphical view]
    PfamiPF07690. MFS_1. 1 hit.
    [Graphical view]
    SUPFAMiSSF103473. SSF103473. 1 hit.
    PROSITEiPS50850. MFS. 1 hit.
    [Graphical view]
    ProtoNetiSearch...

    Entry informationi

    Entry nameiPCFT_HUMAN
    AccessioniPrimary (citable) accession number: Q96NT5
    Secondary accession number(s): Q1HE20
    , Q86T92, Q8TEG3, Q96FL0
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: November 8, 2005
    Last sequence update: December 1, 2001
    Last modified: September 7, 2016
    This is version 126 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

    Complete proteome, Reference proteome

    Documents

    1. Human chromosome 17
      Human chromosome 17: 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. 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.