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Protein

Cytochrome b5 reductase 4

Gene

CYB5R4

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

Functioni

NADH-cytochrome b5 reductase involved in endoplasmic reticulum stress response pathway. Plays a critical role in protecting pancreatic beta-cells against oxidant stress, possibly by protecting the cell from excess buildup of reactive oxygen species (ROS). Reduces a variety of substrates in vitro, such as cytochrome c, feericyanide and methemoglobin.

Catalytic activityi

NADH + 2 ferricytochrome b5 = NAD+ + H+ + 2 ferrocytochrome b5.

Cofactori

FAD1 Publication

Redox potential

E0 is -108 mV.

Kineticsi

  1. KM=25 mM for O2

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Metal bindingi89Iron (heme axial ligand)1
    Metal bindingi112Iron (heme axial ligand)1

    Regions

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Nucleotide bindingi365 – 380FADBy similarityAdd BLAST16
    Nucleotide bindingi392 – 424FADBy similarityAdd BLAST33

    GO - Molecular functioni

    • cytochrome-b5 reductase activity, acting on NAD(P)H Source: UniProtKB
    • FAD binding Source: GO_Central
    • heme binding Source: InterPro
    • metal ion binding Source: UniProtKB-KW
    • NAD(P)H oxidase activity Source: UniProtKB
    • oxidoreductase activity, acting on NAD(P)H, heme protein as acceptor Source: UniProtKB

    GO - Biological processi

    • bicarbonate transport Source: Reactome
    • cell development Source: UniProtKB
    • detection of oxygen Source: UniProtKB
    • generation of precursor metabolites and energy Source: UniProtKB
    • glucose homeostasis Source: UniProtKB
    • insulin secretion Source: UniProtKB
    • oxidation-reduction process Source: UniProtKB
    • response to antibiotic Source: UniProtKB
    • superoxide metabolic process Source: UniProtKB
    Complete GO annotation...

    Keywords - Molecular functioni

    Oxidoreductase

    Keywords - Ligandi

    FAD, Flavoprotein, Heme, Iron, Metal-binding, NAD

    Enzyme and pathway databases

    BioCyciZFISH:HS00849-MONOMER.
    BRENDAi1.6.2.2. 2681.
    ReactomeiR-HSA-1237044. Erythrocytes take up carbon dioxide and release oxygen.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Cytochrome b5 reductase 4 (EC:1.6.2.2)
    Alternative name(s):
    Flavohemoprotein b5/b5R
    Short name:
    b5+b5R
    N-terminal cytochrome b5 and cytochrome b5 oxidoreductase domain-containing protein
    cb5/cb5R
    Gene namesi
    Name:CYB5R4
    Synonyms:NCB5OR
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 6

    Organism-specific databases

    HGNCiHGNC:20147. CYB5R4.

    Subcellular locationi

    GO - Cellular componenti

    • endoplasmic reticulum Source: UniProtKB
    • endoplasmic reticulum membrane Source: Reactome
    • perinuclear region of cytoplasm Source: UniProtKB
    Complete GO annotation...

    Keywords - Cellular componenti

    Endoplasmic reticulum

    Pathology & Biotechi

    Organism-specific databases

    DisGeNETi51167.
    OpenTargetsiENSG00000065615.
    PharmGKBiPA134904907.

    Polymorphism and mutation databases

    BioMutaiCYB5R4.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00002875561 – 521Cytochrome b5 reductase 4Add BLAST521

    Amino acid modifications

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

    Keywords - PTMi

    Acetylation

    Proteomic databases

    EPDiQ7L1T6.
    MaxQBiQ7L1T6.
    PaxDbiQ7L1T6.
    PeptideAtlasiQ7L1T6.
    PRIDEiQ7L1T6.
    TopDownProteomicsiQ7L1T6.

    PTM databases

    iPTMnetiQ7L1T6.
    PhosphoSitePlusiQ7L1T6.

    Expressioni

    Tissue specificityi

    Widely expressed.1 Publication

    Gene expression databases

    BgeeiENSG00000065615.
    CleanExiHS_CYB5R4.
    ExpressionAtlasiQ7L1T6. baseline and differential.
    GenevisibleiQ7L1T6. HS.

    Organism-specific databases

    HPAiHPA018992.

    Interactioni

    Protein-protein interaction databases

    BioGridi119347. 1 interactor.
    IntActiQ7L1T6. 1 interactor.
    MINTiMINT-4714403.
    STRINGi9606.ENSP00000358695.

    Structurei

    Secondary structure

    1521
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Beta strandi53 – 57Combined sources5
    Helixi59 – 64Combined sources6
    Beta strandi70 – 75Combined sources6
    Beta strandi78 – 81Combined sources4
    Helixi83 – 85Combined sources3
    Turni86 – 88Combined sources3
    Helixi93 – 97Combined sources5
    Turni98 – 101Combined sources4
    Helixi105 – 112Combined sources8
    Helixi117 – 120Combined sources4
    Helixi122 – 124Combined sources3
    Beta strandi125 – 129Combined sources5
    Helixi133 – 136Combined sources4

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    3LF5X-ray1.25A/B51-137[»]
    ProteinModelPortaliQ7L1T6.
    SMRiQ7L1T6.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiQ7L1T6.

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini54 – 130Cytochrome b5 heme-bindingPROSITE-ProRule annotationAdd BLAST77
    Domaini165 – 256CSPROSITE-ProRule annotationAdd BLAST92
    Domaini273 – 385FAD-binding FR-typePROSITE-ProRule annotationAdd BLAST113

    Sequence similaritiesi

    Contains 1 CS domain.PROSITE-ProRule annotation
    Contains 1 cytochrome b5 heme-binding domain.PROSITE-ProRule annotation
    Contains 1 FAD-binding FR-type domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiKOG0534. Eukaryota.
    KOG0536. Eukaryota.
    COG0543. LUCA.
    COG5274. LUCA.
    GeneTreeiENSGT00390000008881.
    HOGENOMiHOG000230826.
    HOVERGENiHBG108174.
    InParanoidiQ7L1T6.
    KOiK00326.
    OMAiKDYHEEK.
    OrthoDBiEOG091G05LX.
    PhylomeDBiQ7L1T6.
    TreeFamiTF313874.

    Family and domain databases

    Gene3Di2.60.40.790. 1 hit.
    3.10.120.10. 1 hit.
    InterProiIPR007052. CS_dom.
    IPR033566. CYB5R4.
    IPR001199. Cyt_B5-like_heme/steroid-bd.
    IPR018506. Cyt_B5_heme-BS.
    IPR017927. Fd_Rdtase_FAD-bd.
    IPR008978. HSP20-like_chaperone.
    IPR001834. NADH-Cyt_B5_reductase.
    IPR008333. OxRdtase_FAD-bd_dom.
    IPR001433. OxRdtase_FAD/NAD-bd.
    IPR017938. Riboflavin_synthase-like_b-brl.
    [Graphical view]
    PANTHERiPTHR19370:SF122. PTHR19370:SF122. 2 hits.
    PfamiPF04969. CS. 1 hit.
    PF00173. Cyt-b5. 1 hit.
    PF00970. FAD_binding_6. 1 hit.
    PF00175. NAD_binding_1. 1 hit.
    [Graphical view]
    PRINTSiPR00406. CYTB5RDTASE.
    PR00363. CYTOCHROMEB5.
    SMARTiSM01117. Cyt-b5. 1 hit.
    [Graphical view]
    SUPFAMiSSF49764. SSF49764. 1 hit.
    SSF55856. SSF55856. 1 hit.
    SSF63380. SSF63380. 1 hit.
    PROSITEiPS51203. CS. 1 hit.
    PS00191. CYTOCHROME_B5_1. 1 hit.
    PS50255. CYTOCHROME_B5_2. 1 hit.
    PS51384. FAD_FR. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Q7L1T6-1 [UniParc]FASTAAdd to basket

    « Hide

            10         20         30         40         50
    MLNVPSQSFP APRSQQRVAS GGRSKVPLKQ GRSLMDWIRL TKSGKDLTGL
    60 70 80 90 100
    KGRLIEVTEE ELKKHNKKDD CWICIRGFVY NVSPYMEYHP GGEDELMRAA
    110 120 130 140 150
    GSDGTELFDQ VHRWVNYESM LKECLVGRMA IKPAVLKDYR EEEKKVLNGM
    160 170 180 190 200
    LPKSQVTDTL AKEGPSYPSY DWFQTDSLVT IAIYTKQKDI NLDSIIVDHQ
    210 220 230 240 250
    NDSFRAETII KDCLYLIHIG LSHEVQEDFS VRVVESVGKI EIVLQKKENT
    260 270 280 290 300
    SWDFLGHPLK NHNSLIPRKD TGLYYRKCQL ISKEDVTHDT RLFCLMLPPS
    310 320 330 340 350
    THLQVPIGQH VYLKLPITGT EIVKPYTPVS GSLLSEFKEP VLPNNKYIYF
    360 370 380 390 400
    LIKIYPTGLF TPELDRLQIG DFVSVSSPEG NFKISKFQEL EDLFLLAAGT
    410 420 430 440 450
    GFTPMVKILN YALTDIPSLR KVKLMFFNKT EDDIIWRSQL EKLAFKDKRL
    460 470 480 490 500
    DVEFVLSAPI SEWNGKQGHI SPALLSEFLK RNLDKSKVLV CICGPVPFTE
    510 520
    QGVRLLHDLN FSKNEIHSFT A
    Length:521
    Mass (Da):59,474
    Last modified:August 30, 2005 - v1
    Checksum:i9D83BAB387E3B0F4
    GO

    Sequence cautioni

    The sequence AAF04812 differs from that shown. Reason: Erroneous initiation.Curated
    The sequence CAI19905 differs from that shown. Reason: Erroneous gene model prediction.Curated
    The sequence CAI22326 differs from that shown. Reason: Erroneous gene model prediction.Curated

    Polymorphismi

    Variants Arg-187 and Arg-223 do not influence the pathogenesis of non-autoimmune diabetes.1 Publication

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_047967140R → H.1 PublicationCorresponds to variant rs61762820dbSNPEnsembl.1
    Natural variantiVAR_032323187Q → R.1 PublicationCorresponds to variant rs143478181dbSNPEnsembl.1
    Natural variantiVAR_032324223H → R.1 PublicationCorresponds to variant rs141290525dbSNPEnsembl.1
    Natural variantiVAR_047968267P → A.1 PublicationCorresponds to variant rs61382555dbSNPEnsembl.1
    Natural variantiVAR_032325282S → P.Corresponds to variant rs10080628dbSNPEnsembl.1
    Natural variantiVAR_047969316P → S.1 PublicationCorresponds to variant rs10080628dbSNPEnsembl.1
    Natural variantiVAR_036240371D → Y in a breast cancer sample; somatic mutation. 1 Publication1
    Natural variantiVAR_036241390L → M in a breast cancer sample; somatic mutation. 1 Publication1

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    EU448291 Genomic DNA. Translation: ACA06109.1.
    AL139232, AL034347 Genomic DNA. Translation: CAI19904.2.
    AL034347, AL139232 Genomic DNA. Translation: CAI22325.2.
    AL034347, AL139232 Genomic DNA. Translation: CAI22326.1. Sequence problems.
    AL139232, AL034347 Genomic DNA. Translation: CAI19905.1. Sequence problems.
    BC025380 mRNA. Translation: AAH25380.2.
    AF169803 mRNA. Translation: AAF04812.1. Different initiation.
    CCDSiCCDS5000.2.
    RefSeqiNP_057314.2. NM_016230.3.
    UniGeneiHs.5741.

    Genome annotation databases

    EnsembliENST00000369681; ENSP00000358695; ENSG00000065615.
    GeneIDi51167.
    KEGGihsa:51167.
    UCSCiuc003pkf.4. human.

    Keywords - Coding sequence diversityi

    Polymorphism

    Cross-referencesi

    Web resourcesi

    SeattleSNPs

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    EU448291 Genomic DNA. Translation: ACA06109.1.
    AL139232, AL034347 Genomic DNA. Translation: CAI19904.2.
    AL034347, AL139232 Genomic DNA. Translation: CAI22325.2.
    AL034347, AL139232 Genomic DNA. Translation: CAI22326.1. Sequence problems.
    AL139232, AL034347 Genomic DNA. Translation: CAI19905.1. Sequence problems.
    BC025380 mRNA. Translation: AAH25380.2.
    AF169803 mRNA. Translation: AAF04812.1. Different initiation.
    CCDSiCCDS5000.2.
    RefSeqiNP_057314.2. NM_016230.3.
    UniGeneiHs.5741.

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    3LF5X-ray1.25A/B51-137[»]
    ProteinModelPortaliQ7L1T6.
    SMRiQ7L1T6.
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi119347. 1 interactor.
    IntActiQ7L1T6. 1 interactor.
    MINTiMINT-4714403.
    STRINGi9606.ENSP00000358695.

    PTM databases

    iPTMnetiQ7L1T6.
    PhosphoSitePlusiQ7L1T6.

    Polymorphism and mutation databases

    BioMutaiCYB5R4.

    Proteomic databases

    EPDiQ7L1T6.
    MaxQBiQ7L1T6.
    PaxDbiQ7L1T6.
    PeptideAtlasiQ7L1T6.
    PRIDEiQ7L1T6.
    TopDownProteomicsiQ7L1T6.

    Protocols and materials databases

    DNASUi51167.
    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENST00000369681; ENSP00000358695; ENSG00000065615.
    GeneIDi51167.
    KEGGihsa:51167.
    UCSCiuc003pkf.4. human.

    Organism-specific databases

    CTDi51167.
    DisGeNETi51167.
    GeneCardsiCYB5R4.
    HGNCiHGNC:20147. CYB5R4.
    HPAiHPA018992.
    MIMi608343. gene.
    neXtProtiNX_Q7L1T6.
    OpenTargetsiENSG00000065615.
    PharmGKBiPA134904907.
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiKOG0534. Eukaryota.
    KOG0536. Eukaryota.
    COG0543. LUCA.
    COG5274. LUCA.
    GeneTreeiENSGT00390000008881.
    HOGENOMiHOG000230826.
    HOVERGENiHBG108174.
    InParanoidiQ7L1T6.
    KOiK00326.
    OMAiKDYHEEK.
    OrthoDBiEOG091G05LX.
    PhylomeDBiQ7L1T6.
    TreeFamiTF313874.

    Enzyme and pathway databases

    BioCyciZFISH:HS00849-MONOMER.
    BRENDAi1.6.2.2. 2681.
    ReactomeiR-HSA-1237044. Erythrocytes take up carbon dioxide and release oxygen.

    Miscellaneous databases

    EvolutionaryTraceiQ7L1T6.
    GeneWikiiCYB5R4.
    GenomeRNAii51167.
    PROiQ7L1T6.
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSG00000065615.
    CleanExiHS_CYB5R4.
    ExpressionAtlasiQ7L1T6. baseline and differential.
    GenevisibleiQ7L1T6. HS.

    Family and domain databases

    Gene3Di2.60.40.790. 1 hit.
    3.10.120.10. 1 hit.
    InterProiIPR007052. CS_dom.
    IPR033566. CYB5R4.
    IPR001199. Cyt_B5-like_heme/steroid-bd.
    IPR018506. Cyt_B5_heme-BS.
    IPR017927. Fd_Rdtase_FAD-bd.
    IPR008978. HSP20-like_chaperone.
    IPR001834. NADH-Cyt_B5_reductase.
    IPR008333. OxRdtase_FAD-bd_dom.
    IPR001433. OxRdtase_FAD/NAD-bd.
    IPR017938. Riboflavin_synthase-like_b-brl.
    [Graphical view]
    PANTHERiPTHR19370:SF122. PTHR19370:SF122. 2 hits.
    PfamiPF04969. CS. 1 hit.
    PF00173. Cyt-b5. 1 hit.
    PF00970. FAD_binding_6. 1 hit.
    PF00175. NAD_binding_1. 1 hit.
    [Graphical view]
    PRINTSiPR00406. CYTB5RDTASE.
    PR00363. CYTOCHROMEB5.
    SMARTiSM01117. Cyt-b5. 1 hit.
    [Graphical view]
    SUPFAMiSSF49764. SSF49764. 1 hit.
    SSF55856. SSF55856. 1 hit.
    SSF63380. SSF63380. 1 hit.
    PROSITEiPS51203. CS. 1 hit.
    PS00191. CYTOCHROME_B5_1. 1 hit.
    PS50255. CYTOCHROME_B5_2. 1 hit.
    PS51384. FAD_FR. 1 hit.
    [Graphical view]
    ProtoNetiSearch...

    Entry informationi

    Entry nameiNB5R4_HUMAN
    AccessioniPrimary (citable) accession number: Q7L1T6
    Secondary accession number(s): B1AEM2
    , Q5TGI9, Q9NUE4, Q9UHI9
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: May 15, 2007
    Last sequence update: August 30, 2005
    Last modified: November 2, 2016
    This is version 112 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 6
      Human chromosome 6: 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.