Q7L1T6 (NB5R4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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 names

Name:	CYB5R4
Synonyms:	NCB5OR

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	521 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	NADH-cytochrome b5 reductase involved in endolasmic 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 activity	NADH + 2 ferricytochrome b5 = NAD+ + H+ + 2 ferrocytochrome b5.
Cofactor	FAD.
Subcellular location	Endoplasmic reticulum. Note: Soluble protein. Ref.4 Ref.6
Tissue specificity	Widely expressed. Ref.4
Polymorphism	Variants Arg-187 and Arg-223 do not influence the pathogenesis of non-autoimmune diabetes.
Sequence similarities	Belongs to the flavoprotein pyridine nucleotide cytochrome reductase family. Contains 1 CS domain. Contains 1 cytochrome b5 heme-binding domain. Contains 1 FAD-binding FR-type domain.
Biophysicochemical properties	Kinetic parameters: KM=25 mM for O2 Redox potential: E0 is -108 mV.
Sequence caution	The sequence AAF04812.1 differs from that shown. Reason: Erroneous initiation. The sequence CAI19905.1 differs from that shown. Reason: Erroneous gene model prediction. The sequence CAI22326.1 differs from that shown. Reason: Erroneous gene model prediction.

Ontologies

Keywords
Cellular component	Endoplasmic reticulum
Coding sequence diversity	Polymorphism
Ligand	FAD Flavoprotein Heme Iron Metal-binding NAD
Molecular function	Oxidoreductase
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	cell development Inferred from sequence or structural similarity. Source: UniProtKB detection of oxygen Non-traceable author statement Ref.4. Source: UniProtKB generation of precursor metabolites and energy Inferred from direct assay Ref.4. Source: UniProtKB glucose homeostasis Inferred from sequence or structural similarity. Source: UniProtKB insulin secretion Inferred from sequence or structural similarity. Source: UniProtKB response to antibiotic Inferred from sequence or structural similarity. Source: UniProtKB superoxide metabolic process Inferred from direct assay Ref.4. Source: UniProtKB
Cellular component	endoplasmic reticulum Inferred from direct assay Ref.6. Source: UniProtKB perinuclear region of cytoplasm Inferred from direct assay Ref.4. Source: UniProtKB
Molecular function	NAD(P)H oxidase activity Inferred from direct assay Ref.4Ref.6. Source: UniProtKB cytochrome-b5 reductase activity Inferred from direct assay Ref.4. Source: UniProtKB heme binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 521

521

Cytochrome b5 reductase 4

PRO_0000287556

Regions

Domain

54 – 130

77

Cytochrome b5 heme-binding

Domain

165 – 256

92

CS

Domain

273 – 385

113

FAD-binding FR-type

Nucleotide binding

365 – 380

16

FAD By similarity

Nucleotide binding

392 – 424

33

FAD By similarity

Sites

Metal binding

89

1

Iron (heme axial ligand) By similarity

Metal binding

112

1

Iron (heme axial ligand) By similarity

Natural variations

Natural variant

140

1

R → H. Ref.1

VAR_047967

Natural variant

187

1

Q → R. Ref.5

VAR_032323

Natural variant

223

1

H → R. Ref.5

VAR_032324

Natural variant

267

1

P → A. Ref.1
Corresponds to variant rs61382555 [ dbSNP | Ensembl ].

VAR_047968

Natural variant

282

1

S → P.
Corresponds to variant rs10080628 [ dbSNP | Ensembl ].

VAR_032325

Natural variant

316

1

P → S. Ref.1
Corresponds to variant rs10080628 [ dbSNP | Ensembl ].

VAR_047969

Natural variant

371

1

D → Y in a breast cancer sample; somatic mutation. Ref.7

VAR_036240

Natural variant

390

1

L → M in a breast cancer sample; somatic mutation. Ref.7

VAR_036241

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

521

Helix Strand Turn

Details...

Helix

59 – 64

6

Beta strand

70 – 74

5

Beta strand

79 – 81

3

Helix

83 – 85

3

Turn

86 – 88

3

Helix

94 – 97

4

Helix

106 – 112

7

Helix

117 – 120

4

Helix

122 – 124

3

Helix

133 – 136

4

Sequences

	Sequence		Length	Mass (Da)
	Q7L1T6 [UniParc]. Last modified August 30, 2005. Version 1. Checksum: 9D83BAB387E3B0F4	FASTA	521	59,474
	10 20 30 40 50 60 MLNVPSQSFP APRSQQRVAS GGRSKVPLKQ GRSLMDWIRL TKSGKDLTGL KGRLIEVTEE 70 80 90 100 110 120 ELKKHNKKDD CWICIRGFVY NVSPYMEYHP GGEDELMRAA GSDGTELFDQ VHRWVNYESM 130 140 150 160 170 180 LKECLVGRMA IKPAVLKDYR EEEKKVLNGM LPKSQVTDTL AKEGPSYPSY DWFQTDSLVT 190 200 210 220 230 240 IAIYTKQKDI NLDSIIVDHQ NDSFRAETII KDCLYLIHIG LSHEVQEDFS VRVVESVGKI 250 260 270 280 290 300 EIVLQKKENT SWDFLGHPLK NHNSLIPRKD TGLYYRKCQL ISKEDVTHDT RLFCLMLPPS 310 320 330 340 350 360 THLQVPIGQH VYLKLPITGT EIVKPYTPVS GSLLSEFKEP VLPNNKYIYF LIKIYPTGLF 370 380 390 400 410 420 TPELDRLQIG DFVSVSSPEG NFKISKFQEL EDLFLLAAGT GFTPMVKILN YALTDIPSLR 430 440 450 460 470 480 KVKLMFFNKT EDDIIWRSQL EKLAFKDKRL DVEFVLSAPI SEWNGKQGHI SPALLSEFLK 490 500 510 520 RNLDKSKVLV CICGPVPFTE QGVRLLHDLN FSKNEIHSFT A

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	SeattleSNPs variation discovery resource Submitted (FEB-2008) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS HIS-140; ALA-267 AND SER-316.
[2]	"The DNA sequence and analysis of human chromosome 6." Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., Andrews T.D. , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S. Nature 425:805-811(2003) [PubMed: 14574404] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Testis.
[4]	"Identification of a cytochrome b-type NAD(P)H oxidoreductase ubiquitously expressed in human cells." Zhu H., Qiu H., Yoon H.-W., Huang S., Bunn H.F. Proc. Natl. Acad. Sci. U.S.A. 96:14742-14747(1999) [PubMed: 10611283] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 33-521, SUBCELLULAR LOCATION, HEME-BINDING, FAD-BINDING, TISSUE SPECIFICITY.
[5]	"Variation in NCB5OR: studies of relationships to type 2 diabetes, maturity-onset diabetes of the young, and gestational diabetes mellitus." Andersen G., Wegner L., Rose C.S., Xie J., Zhu H., Larade K., Johansen A., Ek J., Lauenborg J., Drivsholm T., Borch-Johnsen K., Damm P., Hansen T., Bunn H.F., Pedersen O. Diabetes 53:2992-2997(2004) [PubMed: 15504981] [Abstract] Cited for: VARIANTS ARG-187 AND ARG-223.
[6]	"NCB5OR is a novel soluble NAD(P)H reductase localized in the endoplasmic reticulum." Zhu H., Larade K., Jackson T.A., Xie J., Ladoux A., Acker H., Berchner-Pfannschmidt U., Fandrey J., Cross A.R., Lukat-Rodgers G.S., Rodgers K.R., Bunn H.F. J. Biol. Chem. 279:30316-30325(2004) [PubMed: 15131110] [Abstract] Cited for: SUBCELLULAR LOCATION.
[7]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed: 16959974] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] TYR-371 AND MET-390.
+	Additional computationally mapped references.

Web resources

SeattleSNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

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.

IPI

IPI00008236.

RefSeq

NP_057314.2. NM_016230.3.

UniGene

Hs.5741.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3LF5	X-ray	1.25	A/B	51-137	[»]

ProteinModelPortal

Q7L1T6.

SMR

Q7L1T6. Positions 51-137, 167-255, 271-519.

ModBase

Search...

Protein-protein interaction databases

STRING

Q7L1T6.

PTM databases

PhosphoSite

Q7L1T6.

Polymorphism databases

DMDM

121944420.

Proteomic databases

PRIDE

Q7L1T6.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000369681; ENSP00000358695; ENSG00000065615.

GeneID

51167.

KEGG

hsa:51167.

NMPDR

fig|9606.3.peg.27467.

UCSC

uc003pkf.1. human.

Organism-specific databases

CTD

51167.

GeneCards

GC06P084569.

H-InvDB

HIX0006039.

HGNC

HGNC:20147. CYB5R4.

HPA

HPA018992.

MIM

608343. gene.

neXtProt

NX_Q7L1T6.

PharmGKB

PA134904907.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG12233.

GeneTree

ENSGT00390000008881.

HOGENOM

HBG717192.

HOVERGEN

HBG108174.

InParanoid

Q7L1T6.

OMA

ATGNPRN.

OrthoDB

EOG49CQ7B.

PhylomeDB

Q7L1T6.

Gene expression databases

ArrayExpress

Q7L1T6.

Bgee

Q7L1T6.

CleanEx

HS_CYB5R4.

Genevestigator

Q7L1T6.

Family and domain databases

InterPro

IPR007052. CS-like_domain.
IPR017447. CS_domain.
IPR001199. Cyt_B5.
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]

Gene3D

G3DSA:3.10.120.10. Cyt_B5. 1 hit.

Pfam

PF04969. CS. 1 hit.
PF00173. Cyt-b5. 1 hit.
PF00970. FAD_binding_6. 1 hit.
PF00175. NAD_binding_1. 1 hit.
[Graphical view]

PRINTS

PR00406. CYTB5RDTASE.
PR00363. CYTOCHROMEB5.

SUPFAM

SSF55856. Cyt_B5. 1 hit.
SSF49764. HSP20_chap. 1 hit.
SSF63380. Riboflavin_synthase_like_b-brl. 1 hit.

PROSITE

PS51203. CS. 1 hit.
PS00191. CYTOCHROME_B5_1. 1 hit.
PS50255. CYTOCHROME_B5_2. 1 hit.
PS51384. FAD_FR. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

NextBio

54103.

SOURCE

Search...

Entry information

Entry name

NB5R4_HUMAN

Accession

Primary (citable) accession number: Q7L1T6
Secondary accession number(s): B1AEM2 , Q5TGI9, Q9NUE4, Q9UHI9

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 15, 2007
Last sequence update:	August 30, 2005
Last modified:	January 25, 2012
This is version 66 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.