P31350 (RIR2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Ribonucleoside-diphosphate reductase subunit M2
EC=1.17.4.1

Alternative name(s):
Ribonucleotide reductase small chain
Ribonucleotide reductase small subunit

Gene names

Name:	RRM2
Synonyms:	RR2

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	389 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Provides the precursors necessary for DNA synthesis. Catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides. Inhibits Wnt signaling.
Catalytic activity	2'-deoxyribonucleoside diphosphate + thioredoxin disulfide + H2O = ribonucleoside diphosphate + thioredoxin.
Cofactor	Binds 2 iron ions per subunit By similarity.
Pathway	Genetic information processing; DNA replication.
Subunit structure	Heterodimer of a large and a small subunit.
Subcellular location	Cytoplasm.
Post-translational modification	Phosphorylation on Ser-20 relieves the inhibitory effect on Wnt signaling.
Miscellaneous	Two distinct regulatory sites have been defined: the specificity site, which controls substrate specificity, and the activity site which regulates overall catalytic activity. A substrate-binding catalytic site, located on M1, is formed only in the presence of the second subunit M2.
Sequence similarities	Belongs to the ribonucleoside diphosphate reductase small chain family.
Sequence caution	The sequence DA477511 differs from that shown. Reason: Frameshift at position 87.

Ontologies

Keywords
Biological process	DNA replication
Cellular component	Cytoplasm
Coding sequence diversity	Alternative splicing
Ligand	Iron Metal-binding
Molecular function	Oxidoreductase
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	DNA replication Non-traceable author statement. Source: UniProtKB deoxyribonucleoside diphosphate metabolic process Inferred from electronic annotation. Source: InterPro deoxyribonucleotide biosynthetic process Inferred from sequence or structural similarity. Source: UniProtKB nucleobase-containing small molecule interconversion Traceable author statement. Source: Reactome regulation of transcription involved in G1/S phase of mitotic cell cycle Traceable author statement. Source: Reactome
Cellular_component	cytosol Traceable author statement. Source: Reactome nucleoplasm Traceable author statement. Source: Reactome ribonucleoside-diphosphate reductase complex Inferred from electronic annotation. Source: InterPro
Molecular_function	ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor Inferred from sequence or structural similarity. Source: UniProtKB transition metal ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CCNF	P41002	12	EBI-2339245,EBI-1207574
FZR1	Q9UM11	2	EBI-2339245,EBI-724997
RRM1	P23921	3	EBI-2339245,EBI-717006

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P31350-1)

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: P31350-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-1: M → MGRVGGMAQPMGRAGAPKPMGRAGSARRGRFKGCWSEGSPVHPVPAVLSWLLALLRCASTM

Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 389

389

Ribonucleoside-diphosphate reductase subunit M2

PRO_0000190447

Sites

Active site

176

1

By similarity

Metal binding

138

1

Iron 1 By similarity

Metal binding

169

1

Iron 1 By similarity

Metal binding

169

1

Iron 2 By similarity

Metal binding

172

1

Iron 1 By similarity

Metal binding

232

1

Iron 2 By similarity

Metal binding

266

1

Iron 2 By similarity

Metal binding

269

1

Iron 2 By similarity

Amino acid modifications

Modified residue

20

1

Phosphoserine Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.14

Modified residue

33

1

Phosphothreonine Ref.9 Ref.14

Natural variations

Alternative sequence

1

1

M → MGRVGGMAQPMGRAGAPKPM GRAGSARRGRFKGCWSEGSP VHPVPAVLSWLLALLRCAST M in isoform 2.

VSP_044917

Experimental info

Mutagenesis

20

1

S → A: Enhances inhibitory effect on Wnt signaling.

Mutagenesis

20

1

S → E: Prevents inhibitory effect on Wnt signaling.

Isoform 2:

Sequence conflict

28

1

R → H in DA477511. Ref.3

Sequence conflict

59

1

S → A in DA477511. Ref.3

Secondary structure

1

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389

Helix Strand Turn

Details...

Turn

71 – 73

3

Turn

77 – 80

4

Helix

88 – 99

12

Helix

104 – 106

3

Helix

110 – 112

3

Helix

113 – 118

6

Helix

121 – 147

27

Helix

149 – 152

4

Helix

156 – 183

28

Helix

187 – 194

8

Helix

196 – 199

4

Helix

201 – 203

3

Helix

204 – 215

12

Beta strand

217 – 219

3

Helix

221 – 233

13

Turn

234 – 236

3

Helix

237 – 248

12

Helix

253 – 278

26

Helix

286 – 305

20

Helix

310 – 313

4

Helix

317 – 335

19

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified July 1, 1993. Version 1. Checksum: 10E6F5F84D34DA94	FASTA	389	44,878
	10 20 30 40 50 60 MLSLRVPLAP ITDPQQLQLS PLKGLSLVDK ENTPPALSGT RVLASKTARR IFQEPTEPKT 70 80 90 100 110 120 KAAAPGVEDE PLLRENPRRF VIFPIEYHDI WQMYKKAEAS FWTAEEVDLS KDIQHWESLK 130 140 150 160 170 180 PEERYFISHV LAFFAASDGI VNENLVERFS QEVQITEARC FYGFQIAMEN IHSEMYSLLI 190 200 210 220 230 240 DTYIKDPKER EFLFNAIETM PCVKKKADWA LRWIGDKEAT YGERVVAFAA VEGIFFSGSF 250 260 270 280 290 300 ASIFWLKKRG LMPGLTFSNE LISRDEGLHC DFACLMFKHL VHKPSEERVR EIIINAVRIE 310 320 330 340 350 360 QEFLTEALPV KLIGMNCTLM KQYIEFVADR LMLELGFSKV FRVENPFDFM ENISLEGKTN 370 380 FFEKRVGEYQ RMGVMSSPTE NSFTLDADF
	Isoform 2 [UniParc]. Checksum: DFEA2E41A26BD80E	FASTA	449	51,093
	10 20 30 40 50 60 MGRVGGMAQP MGRAGAPKPM GRAGSARRGR FKGCWSEGSP VHPVPAVLSW LLALLRCAST 70 80 90 100 110 120 MLSLRVPLAP ITDPQQLQLS PLKGLSLVDK ENTPPALSGT RVLASKTARR IFQEPTEPKT 130 140 150 160 170 180 KAAAPGVEDE PLLRENPRRF VIFPIEYHDI WQMYKKAEAS FWTAEEVDLS KDIQHWESLK 190 200 210 220 230 240 PEERYFISHV LAFFAASDGI VNENLVERFS QEVQITEARC FYGFQIAMEN IHSEMYSLLI 250 260 270 280 290 300 DTYIKDPKER EFLFNAIETM PCVKKKADWA LRWIGDKEAT YGERVVAFAA VEGIFFSGSF 310 320 330 340 350 360 ASIFWLKKRG LMPGLTFSNE LISRDEGLHC DFACLMFKHL VHKPSEERVR EIIINAVRIE 370 380 390 400 410 420 QEFLTEALPV KLIGMNCTLM KQYIEFVADR LMLELGFSKV FRVENPFDFM ENISLEGKTN 430 440 FFEKRVGEYQ RMGVMSSPTE NSFTLDADF

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Sequence analysis of the large and small subunits of human ribonucleotide reductase." Pavloff N., Rivard D., Masson S., Shen S.-H., Mes-Masson A.-M. DNA Seq. 2:227-234(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Mammary carcinoma.
[2]	"Characterization of the human ribonucleotide reductase M2 subunit gene; genomic structure and promoter analyses." Zhou B., Yen Y. Cytogenet. Cell Genet. 95:52-59(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-94 (ISOFORM 2). Tissue: Neonatal skin.
[4]	"Generation and annotation of the DNA sequences of human chromosomes 2 and 4." Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H. , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K. Nature 434:724-731(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Muscle and Skin.
[6]	"A probability-based approach for high-throughput protein phosphorylation analysis and site localization." Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P. Nat. Biotechnol. 24:1285-1292(2006) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-20, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[7]	"Improved titanium dioxide enrichment of phosphopeptides from HeLa cells and high confident phosphopeptide identification by cross-validation of MS/MS and MS/MS/MS spectra." Yu L.-R., Zhu Z., Chan K.C., Issaq H.J., Dimitrov D.S., Veenstra T.D. J. Proteome Res. 6:4150-4162(2007) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-20, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[8]	"Quantitative phosphoproteome profiling of Wnt3a-mediated signaling network: indicating the involvement of ribonucleoside-diphosphate reductase M2 subunit phosphorylation at residue serine 20 in canonical Wnt signal transduction." Tang L.-Y., Deng N., Wang L.-S., Dai J., Wang Z.-L., Jiang X.-S., Li S.-J., Li L., Sheng Q.-H., Wu D.-Q., Li L., Zeng R. Mol. Cell. Proteomics 6:1952-1967(2007) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-20, MASS SPECTROMETRY. Tissue: Embryonic kidney.
[9]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-20 AND THR-33, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[10]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-20, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[11]	"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions." Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K. Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-20, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[12]	"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis." Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M. Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-20, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[13]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[14]	"System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation." Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B. Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-20 AND THR-33, MASS SPECTROMETRY.
+	Additional computationally mapped references.

Web resources

Wikipedia

Ribonucleotide reductase entry

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X59618 mRNA. Translation: CAA42181.1.
S40301 mRNA. Translation: AAA09577.1.
AY032750 Genomic DNA. Translation: AAK51163.1.
AK313719 mRNA. Translation: BAG36462.1.
DA477511 mRNA. No translation available.
AC104794 Genomic DNA. Translation: AAX93099.1.
AC118058 Genomic DNA. No translation available.
BC001886 mRNA. Translation: AAH01886.1.
BC030154 mRNA. Translation: AAH30154.1.

IPI

IPI00946732.

PIR

S25854.

RefSeq

NP_001025.1. NM_001034.3.
NP_001159403.1. NM_001165931.1.

UniGene

Hs.226390.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2UW2	X-ray	2.80	A	60-389	[»]
3OLJ	X-ray	2.10	A/B/C/D	66-350	[»]
3VPM	X-ray	2.70	A/B	66-350	[»]
3VPN	X-ray	2.25	A/B	66-350	[»]
3VPO	X-ray	2.30	A/B	66-350	[»]

ProteinModelPortal

P31350.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-24232N.

IntAct

P31350. 7 interactions.

STRING

9606.ENSP00000302955.

PTM databases

PhosphoSite

P31350.

Polymorphism databases

DMDM

400979.

Proteomic databases

PaxDb

P31350.

PRIDE

P31350.

Protocols and materials databases

DNASU

6241.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000304567; ENSP00000302955; ENSG00000171848.
ENST00000360566; ENSP00000353770; ENSG00000171848.

GeneID

6241.

KEGG

hsa:6241.

UCSC

uc021vdr.1. human.

Organism-specific databases

CTD

6241.

GeneCards

GC02P010262.

HGNC

HGNC:10452. RRM2.

HPA

HPA056994.

MIM

180390. gene.

neXtProt

NX_P31350.

PharmGKB

PA299.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0208.

HOGENOM

HOG000255975.

HOVERGEN

HBG001647.

InParanoid

P31350.

KO

K10808.

OMA

YIADWRL.

OrthoDB

EOG4BCDN7.

Enzyme and pathway databases

Reactome

REACT_111217. Metabolism.
REACT_115566. Cell Cycle.

UniPathway

UPA00326.

Gene expression databases

ArrayExpress

P31350.

Bgee

P31350.

CleanEx

HS_RRM2.

Genevestigator

P31350.

GermOnline

ENSG00000171848. Homo sapiens.

Family and domain databases

Gene3D

1.10.620.20. 1 hit.

InterPro

IPR009078. Ferritin-like_SF.
IPR012348. RNR-rel.
IPR000358. RNR_small.
[Graphical view]

PANTHER

PTHR23409. PTHR23409. 1 hit.

Pfam

PF00268. Ribonuc_red_sm. 1 hit.
[Graphical view]

SUPFAM

SSF47240. Ferritin/RR_like. 1 hit.

PROSITE

PS00368. RIBORED_SMALL. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P31350.

ChEMBL

CHEMBL1954.

EvolutionaryTrace

P31350.

GenomeRNAi

6241.

NextBio

24237.

PMAP-CutDB

P31350.

SOURCE

Search...

Entry information

Entry name

RIR2_HUMAN

Accession

Primary (citable) accession number: P31350
Secondary accession number(s): B2R9B5, J3KP43, Q5WRU7

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 1, 1993
Last sequence update:	July 1, 1993
Last modified:	May 1, 2013
This is version 140 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.