Reviewed, UniProtKB/Swiss-Prot P31350 (RIR2_HUMAN)

Names and origin

Protein names

Recommended name:
    Ribonucleoside-diphosphate reductase subunit M2
    EC=1.17.4.1
Alternative name(s):
    Ribonucleotide reductase small subunit
    Ribonucleotide reductase small chain

Gene names

Name:	RRM2
Synonyms:	RR2

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	389 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
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. Ref.8
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.
Involvement in disease	Ribonucleotide reductase is thought to mediate the pathogenesis of the immunodeficiency of adenosine deaminase or purine nucleoside phosphorylase. The deoxynucleotides that accumulate in the lymphoid cells of these patients are thought to feed-back inhibit ribonucleotide reductase, preventing DNA replication and cell proliferation.
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.

Ontologies

Keywords
Biological process	DNA replication
Cellular component	Cytoplasm
Ligand	Iron Metal-binding
Molecular function	Oxidoreductase
PTM	Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	DNA replication Non-traceable author statement. Source: UniProtKB deoxyribonucleoside diphosphate metabolic process Inferred from electronic annotation. Source: InterPro oxidation reduction Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	cytosol Inferred from Experiment. Source: Reactome
Molecular function	iron ion binding Inferred from electronic annotation. Source: UniProtKB-KW ribonucleoside-diphosphate reductase activity Ref.1 Non-traceable author statement. Source: UniProtKB
Complete GO annotation...

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.8 Ref.6 Ref.7 Ref.9 Ref.10 Ref.11

Modified residue

33

1

Phosphothreonine Ref.11

Modified residue

377

1

Phosphoserine Ref.11

Experimental info

Mutagenesis

20

1

S → A: Enhances inhibitory effect on Wnt signaling. Ref.8

Mutagenesis

20

1

S → E: Prevents inhibitory effect on Wnt signaling. Ref.8

Secondary structure

1

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389

Helix Strand Turn

Details...

Turn

71 – 73

3

Helix

88 – 99

12

Helix

104 – 106

3

Helix

110 – 112

3

Helix

113 – 117

5

Helix

122 – 147

26

Helix

149 – 152

4

Helix

156 – 183

28

Helix

187 – 190

4

Turn

201 – 203

3

Helix

204 – 206

3

Turn

207 – 209

3

Helix

210 – 215

6

Beta strand

217 – 219

3

Helix

221 – 233

13

Turn

234 – 236

3

Helix

237 – 247

11

Helix

253 – 278

26

Helix

286 – 305

20

Helix

310 – 313

4

Helix

317 – 334

18

Sequences

	Sequence		Length	Mass (Da)
	P31350-1 [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

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: 1627826] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. 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: 11978970] [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: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[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: 15815621] [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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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: 16964243] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-20, MASS SPECTROMETRY. Tissue: Epithelium.
[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: 17924679] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-20, MASS SPECTROMETRY. Tissue: Epithelium.
[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: 17693683] [Abstract] Cited for: FUNCTION IN WNT SIGNALING INHIBITION, PHOSPHORYLATION AT SER-20, MUTAGENESIS OF SER-20, MASS SPECTROMETRY.
[9]	"Automated phosphoproteome analysis for cultured cancer cells by two-dimensional nanoLC-MS using a calcined titania/C18 biphasic column." Imami K., Sugiyama N., Kyono Y., Tomita M., Ishihama Y. Anal. Sci. 24:161-166(2008) [PubMed: 18187866] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-20, MASS SPECTROMETRY.
[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: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-20, MASS SPECTROMETRY.
[11]	"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: 18691976] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-20; THR-33 AND SER-377, MASS SPECTROMETRY.
[12]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
+	Additional computationally mapped references.

Web resources

Wikipedia

Ribonucleotide reductase entry

Cross-references

Sequence databases

EMBLGenBankDDBJ

X59618 mRNA. Translation: CAA42181.1.
S40301 mRNA. Translation: AAA09577.1.
AY032750 Genomic DNA. Translation: AAK51163.1.
AK313719 mRNA. Translation: BAG36462.1.
AC104794 Genomic DNA. Translation: AAX93099.1.
BC001886 mRNA. Translation: AAH01886.1.
BC030154 mRNA. Translation: AAH30154.1.

IPI

IPI00011118.

PIR

S25854.

RefSeq

NP_001025.1.

UniGene

Hs.226390

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2UW2	X-ray	2.80	A	60-389	[»]

ModBase

Search...

Protein-protein interaction databases

DIP

DIP:24232N.

PTM databases

PhosphoSite

P31350.

Proteomic databases

PRIDE

P31350.

Genome annotation databases

Ensembl

ENSG00000171848. Homo sapiens. [Contig view]

GeneID

6241.

KEGG

hsa:6241.

NMPDR

fig|9606.3.peg.17505.

Organism-specific databases

GeneCards

GC02P010179.

H-InvDB

HIX0001816.

HGNC

HGNC:10452. RRM2.

MIM

180390. gene.

PharmGKB

PA299.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P31350.

HOVERGEN

P31350.

Enzyme and pathway databases

BRENDA

1.17.4.1. 247.

Reactome

REACT_152. Cell Cycle, Mitotic.
REACT_1698. Nucleotide metabolism.

Gene expression databases

ArrayExpress

P31350.

Bgee

P31350.

CleanEx

HS_RRM2.

GermOnline

ENSG00000171848. Homo sapiens.

Family and domain databases

InterPro

IPR012348. Ribncl_red_rel.
IPR000358. Ribonucl_redctse.
[Graphical view]

Gene3D

G3DSA:1.10.620.20. Ribncl_red_rel. 1 hit.

PANTHER

PTHR23409. Ribonucl_redctse. 1 hit.

Pfam

PF00268. Ribonuc_red_sm. 1 hit.
[Graphical view]

PROSITE

PS00368. RIBORED_SMALL. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

24237.

PMAP-CutDB

P31350.

SOURCE

Search...

Entry information

Entry name

RIR2_HUMAN

Accession

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

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 1, 1993
Last sequence update:	July 1, 1993
Last modified:	June 16, 2009
This is version 97 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)