Reviewed, UniProtKB/Swiss-Prot Q05823 (RN5A_HUMAN)

Names and origin

Protein names

Recommended name:
    2-5A-dependent ribonuclease
      Short name=2-5A-dependent RNase
    EC=3.1.26.-
Alternative name(s):
    Ribonuclease L
      Short name=RNase L
    Ribonuclease 4

Gene names

Name:	RNASEL
Synonyms:	RNS4

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	741 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Endoribonuclease, mediator of interferon action, which play a role in mediating resistance to virus infection and apoptosis. Might play a central role in the regulation of mRNA turnover. Ref.4
Catalytic activity	Cleaves 3' of UpNp dimers, with preference for UU and UA sequences, to sets of discrete products ranging from between 4 and 22 nucleotides in length.
Cofactor	Manganese or magnesium. Required for optimal RNA cleavage rates.
Enzyme regulation	After binding to 2-5A (5'-phosphorylated 2',5'-linked oligoadenylates) the homodimerization and subsequent activation occurs. Inhibited by RNase L inhibitor.
Subunit structure	Monomer (inactive form) or homodimer.
Subcellular location	Cytoplasm. Mitochondrion. Ref.4
Tissue specificity	Highly expressed in spleen and thymus followed by prostate, testis, uterus, small intestine, colon and peripheral blood leukocytes.
Induction	By interferons.
Domain	The protein kinase domain is predicted to be catalytically inactive. It allows the homodimerization. The nine ankyrin repeats also called 2-5A sensor constitute the 2-5A binding domain.
Involvement in disease	Defects in RNASEL may be the cause of susceptibility to hereditary prostate cancer 1 (HPC1) [MIM:176807, 601518].
Sequence similarities	Belongs to the protein kinase superfamily. Contains 9 ANK repeats. Contains 1 KEN domain. Contains 1 protein kinase domain.

Ontologies

Keywords
Cellular component	Cytoplasm Mitochondrion
Coding sequence diversity	Polymorphism
Domain	ANK repeat Repeat Zinc-finger
Ligand	ATP-binding Metal-binding Nucleotide-binding RNA-binding Zinc
Molecular function	Endonuclease Hydrolase Nuclease
Technical term	3D-structure
Gene Ontology (GO)
Biological process	mRNA processing Inferred from electronic annotation. Source: InterPro protein amino acid phosphorylation Ref.3 Non-traceable author statement. Source: UniProtKB
Cellular component	mitochondrion Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW RNA binding Ref.3 Inferred from direct assay. Source: UniProtKB endoribonuclease activity, producing 5'-phosphomonoesters Inferred from electronic annotation. Source: InterPro protein kinase activity Inferred from electronic annotation. Source: InterPro zinc ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 741

741

2-5A-dependent ribonuclease

PRO_0000067051

Regions

Repeat

24 – 53

30

ANK 1

Repeat

58 – 87

30

ANK 2

Repeat

91 – 120

30

ANK 3

Repeat

124 – 153

30

ANK 4

Repeat

167 – 197

31

ANK 5

Repeat

201 – 234

34

ANK 6

Repeat

238 – 268

31

ANK 7

Repeat

272 – 301

30

ANK 8

Repeat

303 – 329

27

ANK 9

Domain

365 – 586

222

Protein kinase

Domain

589 – 723

135

KEN

Zinc finger

395 – 444

50

C6-type; atypical

Region

229 – 242

14

2-5A binding (P-loop) 1

Region

253 – 275

23

2-5A binding (P-loop) 2

Natural variations

Natural variant

59

1

G → S Ref.9 Ref.10

VAR_013509

Natural variant

97

1

I → L Ref.12

VAR_042358

Natural variant

289

1

A → T Ref.12

VAR_042359

Natural variant

406

1

S → F Ref.9

VAR_013510

Natural variant

462

1

R → Q Risk factor for prostate cancer; reduced enzymatic activity. dbSNP rs486907. Ref.9 Ref.10 Ref.12 Ref.11

VAR_012056

Natural variant

541

1

D → E No change in enzymatic activity. dbSNP rs627928. Ref.9 Ref.10 Ref.12 Ref.11

VAR_012057

Natural variant

592

1

R → H Ref.12

VAR_042360

Experimental info

Mutagenesis

240

1

K → N: Reduced 2-5A binding activity; almost complete loss of 2-5A binding activity; when associated with N-274. Ref.1

Mutagenesis

274

1

K → N: Reduced 2-5A binding activity; almost complete loss of 2-5A binding activity; when associated with N-240. Ref.1

Mutagenesis

392

1

K → R: Complete loss of enzymatic activity and enzyme dimerization. No change in binding to 2-5A and RNA. Ref.7

Mutagenesis

583

1

H → A: No change in enzymatic activity. Ref.8

Mutagenesis

584

1

P → A: No change in enzymatic activity. Ref.8

Mutagenesis

632

1

W → A: No change in enzymatic activity. Ref.8

Mutagenesis

661

1

D → A: Complete loss of enzymatic activity. Ref.8

Mutagenesis

667

1

R → A: Complete loss of enzymatic activity. No change in 2-5A binding and enzyme dimerization. Ref.8

Mutagenesis

672

1

H → A: Complete loss of enzymatic activity. No change in 2-5A binding activity and enzyme dimerization. Ref.8

Secondary structure

1

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741

Helix Strand Turn

Details...

Helix

22 – 34

13

Helix

38 – 46

9

Turn

56 – 58

3

Helix

62 – 68

7

Helix

72 – 80

9

Helix

95 – 102

8

Helix

105 – 113

9

Helix

128 – 134

7

Helix

138 – 146

9

Helix

159 – 163

5

Helix

171 – 178

8

Helix

181 – 189

9

Helix

205 – 211

7

Turn

215 – 217

3

Helix

218 – 227

10

Helix

242 – 248

7

Helix

252 – 260

9

Beta strand

261 – 263

3

Helix

276 – 282

7

Helix

286 – 295

10

Sequences

	Sequence		Length	Mass (Da)
	Q05823-1 [UniParc]. Last modified February 1, 1996. Version 2. Checksum: 91385EA307E3CE1D	FASTA	741	83,533
	10 20 30 40 50 60 MESRDHNNPQ EGPTSSSGRR AAVEDNHLLI KAVQNEDVDL VQQLLEGGAN VNFQEEEGGW 70 80 90 100 110 120 TPLHNAVQMS REDIVELLLR HGADPVLRKK NGATPFILAA IAGSVKLLKL FLSKGADVNE 130 140 150 160 170 180 CDFYGFTAFM EAAVYGKVKA LKFLYKRGAN VNLRRKTKED QERLRKGGAT ALMDAAEKGH 190 200 210 220 230 240 VEVLKILLDE MGADVNACDN MGRNALIHAL LSSDDSDVEA ITHLLLDHGA DVNVRGERGK 250 260 270 280 290 300 TPLILAVEKK HLGLVQRLLE QEHIEINDTD SDGKTALLLA VELKLKKIAE LLCKRGASTD 310 320 330 340 350 360 CGDLVMTARR NYDHSLVKVL LSHGAKEDFH PPAEDWKPQS SHWGAALKDL HRIYRPMIGK 370 380 390 400 410 420 LKFFIDEKYK IADTSEGGIY LGFYEKQEVA VKTFCEGSPR AQREVSCLQS SRENSHLVTF 430 440 450 460 470 480 YGSESHRGHL FVCVTLCEQT LEACLDVHRG EDVENEEDEF ARNVLSSIFK AVQELHLSCG 490 500 510 520 530 540 YTHQDLQPQN ILIDSKKAAH LADFDKSIKW AGDPQEVKRD LEDLGRLVLY VVKKGSISFE 550 560 570 580 590 600 DLKAQSNEEV VQLSPDEETK DLIHRLFHPG EHVRDCLSDL LGHPFFWTWE SRYRTLRNVG 610 620 630 640 650 660 NESDIKTRKS ESEILRLLQP GPSEHSKSFD KWTTKINECV MKKMNKFYEK RGNFYQNTVG 670 680 690 700 710 720 DLLKFIRNLG EHIDEEKHKK MKLKIGDPSL YFQKTFPDLV IYVYTKLQNT EYRKHFPQTH 730 740 SPNKPQCDGA GGASGLASPG C

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Expression cloning of 2-5A-dependent RNAase: a uniquely regulated mediator of interferon action." Zhou A., Hassel B.A., Silverman R.H. Cell 72:753-765(1993) [PubMed: 7680958] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], MUTAGENESIS OF LYS-240 AND LYS-274. Tissue: Kidney.
[2]	"Analysis and origins of the human and mouse RNase L genes: mediators of interferon action." Zhou A., Nie H., Silverman R.H. Mamm. Genome 11:989-992(2000) [PubMed: 11063255] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Tissue: Placenta.
[3]	"Intrinsic molecular activities of the interferon-induced 2-5A-dependent RNase." Dong B., Xu L., Zhou A., Hassel B.A., Lee X., Torrence P.F., Silverman R.H. J. Biol. Chem. 269:14153-14158(1994) [PubMed: 7514601] [Abstract] Cited for: CHARACTERIZATION OF RNASEL ACTIVITY.
[4]	"The 2-5A/RNase L/RNase L inhibitor (RNI) pathway regulates mitochondrial mRNAs stability in interferon alpha-treated H9 cells." Le Roy F., Bisbal C., Silhol M., Martinand C., Lebleu B., Salehzada T. J. Biol. Chem. 276:48473-48482(2001) [PubMed: 11585831] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[5]	Erratum Le Roy F., Bisbal C., Silhol M., Martinand C., Lebleu B., Salehzada T. J. Biol. Chem. 277:13354-13354(2002)
[6]	"The 2-5A system in viral infection and apoptosis." Castelli J., Wood K.A., Youle R.J. Biomed. Pharmacother. 52:386-390(1998) [PubMed: 9856285] [Abstract] Cited for: REVIEW.
[7]	"Alternative function of a protein kinase homology domain in 2', 5'-oligoadenylate dependent RNase L." Dong B., Silverman R.H. Nucleic Acids Res. 27:439-445(1999) [PubMed: 9862963] [Abstract] Cited for: MUTAGENESIS OF LYS-392.
[8]	"Basis for regulated RNA cleavage by functional analysis of RNase L and Ire1p." Dong B., Niwa M., Walter P., Silverman R.H. RNA 7:361-373(2001) [PubMed: 11333017] [Abstract] Cited for: MUTAGENESIS OF HIS-583; PRO-584; TRP-632; ASP-661; ARG-667 AND HIS-672.
[9]	"Germline alterations of the RNASEL gene, a candidate HPC1 gene at 1q25, in patients and families with prostate cancer." Roekman A., Ikonen T., Seppaelae E.H., Nupponen N., Autio V., Mononen N., Bailey-Wilson J., Trent J., Carpten J., Matikainen M.P., Koivisto P.A., Tammela T.L.J., Kallioniemi O.-P., Schleutker J. Am. J. Hum. Genet. 70:1299-1304(2002) [PubMed: 11941539] [Abstract] Cited for: VARIANTS SER-59; PHE-406; GLN-462 AND GLU-541.
[10]	"Germline mutations in the ribonuclease L gene in families showing linkage with HPC1." Carpten J., Nupponen N., Isaacs S., Sood R., Robbins C., Xu J., Faruque M., Moses T., Ewing C., Gillanders E., Hu P., Bujnovszky P., Makalowska I., Baffoe-Bonnie A., Faith D., Smith J., Stephan D., Wiley K. , Brownstein M., Gildea D., Kelly B., Jenkins R., Hostetter G., Matikainen M., Schleutker J., Klinger K., Connors T., Xiang Y., Wang Z., De Marzo A., Papadopoulos N., Kallioniemi O.-P., Burk R., Meyers D., Groenberg H., Meltzer P., Silverman R., Bailey-Wilson J., Walsh P., Isaacs W., Trent J. Nat. Genet. 30:181-184(2002) [PubMed: 11799394] [Abstract] Cited for: VARIANTS SER-59; GLN-462 AND GLU-541.
[11]	"RNASEL Arg462Gln variant is implicated in up to 13% of prostate cancer cases." Casey G., Neville P.J., Plummer S.J., Xiang Y., Krumroy L.M., Klein E.A., Catalona W.J., Nupponen N., Carpten J.D., Trent J.M., Silverman R.H., Witte J.S. Nat. Genet. 32:581-583(2002) [PubMed: 12415269] [Abstract] Cited for: CHARACTERIZATION OF VARIANTS GLN-462 AND GLU-541.
[12]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed: 17344846] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] LEU-97; THR-289; GLN-462; GLU-541 AND HIS-592.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBLGenBankDDBJ

L10381 Genomic DNA. Translation: AAA18032.1.

IPI

IPI00015864.

PIR

A45771.

RefSeq

NP_066956.1.

UniGene

Hs.518545

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1WDY	X-ray	1.80	A	21-305	[»]

ModBase

Search...

Proteomic databases

PeptideAtlas

Q05823.

PRIDE

Q05823.

Genome annotation databases

Ensembl

ENSG00000135828. Homo sapiens. [Contig view]

GeneID

6041.

KEGG

hsa:6041.

Organism-specific databases

GeneCards

GC01M180809.

H-InvDB

HIX0028845.

HGNC

HGNC:10050. RNASEL.

HPA

CAB010906.
HPA002633.

MIM

176807. phenotype.
180435. gene.
601518. phenotype.

Orphanet

1331. Prostate cancer, familial.

PharmGKB

PA34418.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

Q05823.

HOVERGEN

Q05823.

OMA

Q05823. NMGRNAL.

Gene expression databases

ArrayExpress

Q05823.

Bgee

Q05823.

CleanEx

HS_RNASEL.

GermOnline

ENSG00000135828. Homo sapiens.

Family and domain databases

InterPro

IPR002110. ANK.
IPR000719. Prot_kinase_core.
IPR017441. Protein_kinase_ATP_BS.
IPR006567. PUG-dom.
IPR010513. RNase_L.
[Graphical view]

Gene3D

G3DSA:1.25.40.20. ANK. 1 hit.

Pfam

PF00023. Ank. 9 hits.
PF06479. Ribonuc_2-5A. 1 hit.
[Graphical view]

ProDom

PD000001. Prot_kinase. 1 hit.
[Graphical view] [Entries sharing at least one domain]

SMART

SM00248. ANK. 8 hits.
SM00580. PUG. 1 hit.
[Graphical view]

PROSITE

PS50297. ANK_REP_REGION. 1 hit.
PS50088. ANK_REPEAT. 6 hits.
PS51392. KEN. 1 hit.
PS00107. PROTEIN_KINASE_ATP. False negative.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

23543.

PMAP-CutDB

Q05823.

SOURCE

Search...

Entry information

Entry name

RN5A_HUMAN

Accession

Primary (citable) accession number: Q05823

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1995
Last sequence update:	February 1, 1996
Last modified:	June 16, 2009
This is version 89 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)