Reviewed, UniProtKB/Swiss-Prot Q3TDX8 (NB5R4_MOUSE)

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
    cb5/cb5R
    N-terminal cytochrome b5 and cytochrome b5 oxidoreductase domain-containing protein

Gene names

Name:	Cyb5r4
Synonyms:	Ncb5or

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus

Protein attributes

Sequence length	536 AA.
Sequence status	Complete.
Protein existence	Evidence at transcript 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). Ref.5
Catalytic activity	NADH + 2 ferricytochrome b5 = NAD+ + H+ + 2 ferrocytochrome b5.
Cofactor	FAD By similarity.
Subcellular location	Endoplasmic reticulum. Note: Soluble protein By similarity.
Tissue specificity	Ubiquitously expressed. Isoform 2 is expressed in testis, brain, skeletal muscle and in the male germline. Ref.4 Ref.6
Disruption phenotype	Mice display insulin-deficient diabetes. Embryos and fetus develop normally. At 4 weeks of age, mice show have normal blood glucose levels but impaired glucose tolerance. Isolated islets have markedly impaired glucose- or arginine-stimulated insulin secretion. By 7 weeks of age, they develop severe hyperglycemia with markedly decreased serum insulin levels and nearly normal insulin tolerance. As the animals age, there is a progressive loss of beta cells in pancreatic islets, but there is no loss of alpha, delta, or PP cells. 4 week-old mice have enhanced sensitivity to the diabetogenic agent streptozotocin. Ref.5
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.

Ontologies

Keywords
Cellular component	Endoplasmic reticulum
Coding sequence diversity	Alternative splicing
Ligand	FAD Flavoprotein Heme Iron Metal-binding NAD
Molecular function	Oxidoreductase
Gene Ontology (GO)
Biological process	cell development Ref.5 Inferred from mutant phenotype. Source: MGI glucose homeostasis Ref.5 Inferred from mutant phenotype. Source: MGI insulin secretion Ref.5 Inferred from mutant phenotype. Source: MGI oxidation reduction Inferred from electronic annotation. Source: UniProtKB-KW response to antibiotic Inferred from mutant phenotype. Source: MGI
Cellular component	endoplasmic reticulum Inferred from direct assay. Source: MGI
Molecular function	cytochrome-b5 reductase activity Inferred from direct assay. Source: MGI heme binding Inferred from electronic annotation. Source: InterPro protein binding Inferred from physical interaction. Source: MGI
Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q3TDX8-1)

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.

Isoform 2 (identifier: Q3TDX8-2)

Also known as: cb5/cb5rDelta12;

The sequence of this isoform differs from the canonical sequence as follows:
     334-384: Missing.

Isoform 3 (identifier: Q3TDX8-3)

The sequence of this isoform differs from the canonical sequence as follows:
     157-164: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 536	536	Cytochrome b5 reductase 4		PRO_0000287557
Regions
	Domain	54 – 130	77	Cytochrome b5 heme-binding
	Domain	180 – 271	92	CS
	Domain	288 – 400	113	FAD-binding FR-type
	Nucleotide binding	380 – 395	16	FAD By similarity
	Nucleotide binding	407 – 439	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
	Alternative sequence	157 – 164	8	Missing in isoform 3.		VSP_025561
	Alternative sequence	334 – 384	51	Missing in isoform 2.		VSP_025562
Experimental info
	Sequence conflict	179	1	G → D in BAC41118. Ref.1
	Sequence conflict	179	1	G → D in BAE39522. Ref.1
	Sequence conflict	179	1	G → D in AAH25438. Ref.2
	Sequence conflict	224	1	V → I in AAH25438. Ref.2
	Sequence conflict	308	1	L → F in BAC37357. Ref.1
	Sequence conflict	308	1	L → F in BAC41118. Ref.1
	Sequence conflict	308	1	L → F in BAE39522. Ref.1
	Sequence conflict	308	1	L → F in AAH25438. Ref.2
	Sequence conflict	344	1	V → L in BAE34044. Ref.1
	Sequence conflict	347	1	S → P in BAE41470. Ref.1
	Sequence conflict	364	1	Y → C in BAC37357. Ref.1
	Sequence conflict	364	1	Y → C in BAC41118. Ref.1
	Sequence conflict	364	1	Y → C in BAE39522. Ref.1
	Sequence conflict	396	1	N → D in BAC37357. Ref.1
	Sequence conflict	396	1	N → D in BAC41118. Ref.1
	Sequence conflict	396	1	N → D in BAE39522. Ref.1
	Sequence conflict	401	1	K → T in AAH25438. Ref.2
	Sequence conflict	446	1	E → D in BAC37357. Ref.1
	Sequence conflict	512	1	P → Q in BAE39522. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified May 15, 2007. Version 2. Checksum: C61316ADB756312B	FASTA	536	60,581
	10 20 30 40 50 60 MLNVPSQAFP APGSQQRVSS QGRSKVPLKQ GRSLMDWIRL TKSGKDLTGL KGGLIEVTEE 70 80 90 100 110 120 ELKKHNKKED CWICIRGFVY NVSPYMEYHP GGEDELMRAA GADGTDLFNE VHRWVNYESM 130 140 150 160 170 180 LKECLVGRMA VKPAVPKDCH EGKRVLNGML PKSQMSDTLP RDVTDTLPRD VTDTLPREGL 190 200 210 220 230 240 SSPSYDWFQT ESSVTIVVYT KQKNISLDSV IVDLQDDSLR AEAVIKDHSY LVHVGLSHEV 250 260 270 280 290 300 QENFSVRVIE NVGKIEIVLQ KKESVSWQCL GDHLEKHDSF IPKKDTGLYY RRCQLISKED 310 320 330 340 350 360 VTHDTRLLCL MLPPSTHLQV PVGQHVYLKL SVTGAEIVKP YTPVSDSLLS DFKEPVLSPN 370 380 390 400 410 420 KYIYFLIKIY PAGLFTPELD RLQIGDFISV SGPEGNFKVS KLQEVEDLFL LAAGTGFTPM 430 440 450 460 470 480 VTVLNYALSH MSSLRKVKLM FFNKTEDDII WRCQLEKLAL REKRFDVEFV LSAPSPEWNG 490 500 510 520 530 KQGHISRALL SEFLQRSSEN SRAFLCICGP TPFTDEGIRL LHDLNFSDDE IHGFTA
	Isoform 2 (cb5/cb5rDelta12). Checksum: A956E9D0E27B4EDC	FASTA	485	54,799
	10 20 30 40 50 60 MLNVPSQAFP APGSQQRVSS QGRSKVPLKQ GRSLMDWIRL TKSGKDLTGL KGGLIEVTEE 70 80 90 100 110 120 ELKKHNKKED CWICIRGFVY NVSPYMEYHP GGEDELMRAA GADGTDLFNE VHRWVNYESM 130 140 150 160 170 180 LKECLVGRMA VKPAVPKDCH EGKRVLNGML PKSQMSDTLP RDVTDTLPRD VTDTLPREGL 190 200 210 220 230 240 SSPSYDWFQT ESSVTIVVYT KQKNISLDSV IVDLQDDSLR AEAVIKDHSY LVHVGLSHEV 250 260 270 280 290 300 QENFSVRVIE NVGKIEIVLQ KKESVSWQCL GDHLEKHDSF IPKKDTGLYY RRCQLISKED 310 320 330 340 350 360 VTHDTRLLCL MLPPSTHLQV PVGQHVYLKL SVTGDFISVS GPEGNFKVSK LQEVEDLFLL 370 380 390 400 410 420 AAGTGFTPMV TVLNYALSHM SSLRKVKLMF FNKTEDDIIW RCQLEKLALR EKRFDVEFVL 430 440 450 460 470 480 SAPSPEWNGK QGHISRALLS EFLQRSSENS RAFLCICGPT PFTDEGIRLL HDLNFSDDEI HGFTA
	Isoform 3. Checksum: B91D89490CEAC327	FASTA	528	59,683
	10 20 30 40 50 60 MLNVPSQAFP APGSQQRVSS QGRSKVPLKQ GRSLMDWIRL TKSGKDLTGL KGGLIEVTEE 70 80 90 100 110 120 ELKKHNKKED CWICIRGFVY NVSPYMEYHP GGEDELMRAA GADGTDLFNE VHRWVNYESM 130 140 150 160 170 180 LKECLVGRMA VKPAVPKDCH EGKRVLNGML PKSQMSDTLP RDVTDTLPRE GLSSPSYDWF 190 200 210 220 230 240 QTESSVTIVV YTKQKNISLD SVIVDLQDDS LRAEAVIKDH SYLVHVGLSH EVQENFSVRV 250 260 270 280 290 300 IENVGKIEIV LQKKESVSWQ CLGDHLEKHD SFIPKKDTGL YYRRCQLISK EDVTHDTRLL 310 320 330 340 350 360 CLMLPPSTHL QVPVGQHVYL KLSVTGAEIV KPYTPVSDSL LSDFKEPVLS PNKYIYFLIK 370 380 390 400 410 420 IYPAGLFTPE LDRLQIGDFI SVSGPEGNFK VSKLQEVEDL FLLAAGTGFT PMVTVLNYAL 430 440 450 460 470 480 SHMSSLRKVK LMFFNKTEDD IIWRCQLEKL ALREKRFDVE FVLSAPSPEW NGKQGHISRA 490 500 510 520 LLSEFLQRSS ENSRAFLCIC GPTPFTDEGI RLLHDLNFSD DEIHGFTA

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y. Science 309:1559-1563(2005) [PubMed: 16141072] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3). Strain: C57BL/6J and NOD. Tissue: Eye, Liver, Spinal cord and Spleen.
[2]	"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] (ISOFORM 1). Strain: Czech II and FVB/N. Tissue: Mammary tumor.
[3]	"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 35-536 (ISOFORM 3).
[4]	"Identification and characterization of a novel splice variant of mouse and rat cytochrome b5/cytochrome b5 reductase." Curry B.J., Roman S.D., Wallace C.A., Scott R., Miriami E., Aitken R.J. Genomics 83:425-438(2004) [PubMed: 14962668] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 35-536 (ISOFORMS 1 AND 2), TISSUE SPECIFICITY. Strain: Swiss. Tissue: Testis.
[5]	"Absence of a reductase, NCB5OR, causes insulin-deficient diabetes." Xie J., Zhu H., Larade K., Ladoux A., Seguritan A., Chu M., Ito S., Bronson R.T., Leiter E.H., Zhang C.-Y., Rosen E.D., Bunn H.F. Proc. Natl. Acad. Sci. U.S.A. 101:10750-10755(2004) [PubMed: 15247412] [Abstract] Cited for: FUNCTION, DISRUPTION PHENOTYPE.
[6]	"Promoter characterization and transcriptional regulation of Ncb5or, a novel reductase necessary for pancreatic beta-cell maintenance." Larade K., Bunn H.F. Biochim. Biophys. Acta 1759:257-262(2006) [PubMed: 16814408] [Abstract] Cited for: TISSUE SPECIFICITY.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AK078682 mRNA. Translation: BAC37357.1. AK090159 mRNA. Translation: BAC41118.1. Different initiation. AK157312 mRNA. Translation: BAE34044.1. Different initiation. AK167436 mRNA. Translation: BAE39522.1. AK169937 mRNA. Translation: BAE41470.1. AK172252 mRNA. Translation: BAE42908.1. Different initiation. BC025438 mRNA. Translation: AAH25438.1. Different initiation. BC002170 mRNA. Translation: AAH02170.1. AF338818 mRNA. Translation: AAK08116.1. AY321368 mRNA. Translation: AAQ83900.1. AY321369 mRNA. Translation: AAQ83901.1.
IPI	IPI00225057. IPI00845740. IPI00845804.
RefSeq	NP_077157.2.
UniGene	Mm.30166 Mm.394780 Mm.477392
3D structure databases
HSSP	HSSP built from PDB template 1SH4 based on UniProtKB P00171.
SMR	Q3TDX8. Positions 54-132, 56-230, 178-270, 280-534.
ModBase	Search...
Protein-protein interaction databases
STRING	Q3TDX8.
Proteomic databases
PRIDE	Q3TDX8.
Genome annotation databases
Ensembl	ENSMUST00000050631; ENSMUSP00000059660; ENSMUSG00000032872; Mus musculus. [Genome view]
GeneID	266690.
KEGG	mmu:266690.
Organism-specific databases
CTD	266690.
MGI	MGI:2386848. Cyb5r4.
Phylogenomic databases
eggNOG	roNOG07055.
HOVERGEN	Q3TDX8.
InParanoid	Q3TDX8.
PhylomeDB	Q3TDX8.
Enzyme and pathway databases
BRENDA	1.6.2.2. 244.
Gene expression databases
ArrayExpress	Q3TDX8.
Bgee	Q3TDX8.
CleanEx	MM_CYB5R4.
Genevestigator	Q3TDX8.
Family and domain databases
InterPro	IPR017447. CS. IPR007052. 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]
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.
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 Resources
NextBio	392180.
SOURCE	Search...

Entry information

Entry name

NB5R4_MOUSE

Accession

Primary (citable) accession number: Q3TDX8
Secondary accession number(s): Q3TJH3 , Q3U012, Q6VXY4, Q6VXY5, Q8BJV8, Q8BTI5, Q8R3H8, Q99LY4, Q99P29

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 15, 2007
Last sequence update:	May 15, 2007
Last modified:	January 19, 2010
This is version 50 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)