Q05823 (RN5A_HUMAN) Reviewed, UniProtKB/Swiss-Prot

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 4
Ribonuclease L
Short name=RNase L

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.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Endoribonuclease that functions in the interferon (IFN) antiviral response. In INF treated and virus infected cells, RNASEL probably mediates its antiviral effects through a combination of direct cleavage of single-stranded viral RNAs, inhibition of protein synthesis through the degradation of rRNA, induction of apoptosis, and induction of other antiviral genes. RNASEL mediated apoptosis is the result of a JNK-dependent stress-response pathway leading to cytochrome c release from mitochondria and caspase-dependent apoptosis. Therefore, activation of RNASEL could lead to elimination of virus infected cells under some circumstances. Might play a central role in the regulation of mRNA. turnover. Ref.5
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 RNASEL inhibitor ABCE1/RLI, a cytoplasmic member of the ATP-binding cassette (ABC) transporter family.
Subunit structure	Monomer (inactive form) or homodimer. Interacts with ABCE1; this interaction inhibits the RNASEL. Ref.4
Subcellular location	Cytoplasm. Mitochondrion Ref.5.
Tissue specificity	Highly expressed in spleen and thymus followed by prostate, testis, uterus, small intestine, colon and peripheral blood leukocytes.
Induction	By interferons. Virus replication in higher vertebrates is restrained by IFNs that cause cells to transcribe genes encoding antiviral proteins, such as 2'-5' oligoadenylate synthetases (OASs). oligoadenylate synthetase is stimulated by dsRNA to produce 5'-phosphorylated, 2'-5'-linked oligoadenylates (2-5A), whose function is to activate RNASEL.
Domain	The nine ankyrin repeats also called 2-5A sensor constitute the N-terminus 2-5A binding domain. The protein kinase domain is predicted to be catalytically inactive. It allows the homodimerization. The ribonuclease domain is located in the C-terminus. A single active nuclease domain in a dimer is sufficient for ribonuclease activity By similarity.
Involvement in disease	Defects in RNASEL are a cause of susceptibility to prostate cancer hereditary type 1 (HPC1) [MIM:601518]. It is a condition associated with familial predisposition to cancer of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell carcinoma and neuroendocrine carcinoma.
Sequence similarities	Belongs to the protein kinase superfamily. Contains 9 ANK repeats. Contains 1 KEN domain. Contains 1 protein kinase domain.

Ontologies

Keywords
Biological process	Antiviral defense
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
PTM	Acetylation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	defense response to virus Inferred from direct assay. Source: UniProtKB mRNA processing Inferred from electronic annotation. Source: InterPro negative regulation of viral genome replication Inferred from direct assay. Source: UniProtKB type I interferon-mediated signaling pathway Traceable author statement. Source: Reactome
Cellular component	cytosol Traceable author statement. Source: Reactome mitochondrion Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW RNA binding Inferred from direct assay Ref.3. Source: UniProtKB endoribonuclease activity, producing 5'-phosphomonoesters Inferred from electronic annotation. Source: InterPro metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW protein kinase activity 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 – 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

Amino acid modifications

Modified residue

684

1

N6-acetyllysine Ref.10

Natural variations

Natural variant

59

1

G → S. Ref.12 Ref.13

VAR_013509

Natural variant

97

1

I → L. Ref.15
Corresponds to variant rs56250729 [ dbSNP | Ensembl ].

VAR_042358

Natural variant

289

1

A → T. Ref.15
Corresponds to variant rs35553278 [ dbSNP | Ensembl ].

VAR_042359

Natural variant

406

1

S → F. Ref.12

VAR_013510

Natural variant

462

1

R → Q Risk factor for prostate cancer; reduced enzymatic activity. Ref.12 Ref.13 Ref.14 Ref.15
Corresponds to variant rs486907 [ dbSNP | Ensembl ].

VAR_012056

Natural variant

541

1

D → E No change in enzymatic activity. Ref.12 Ref.13 Ref.14 Ref.15
Corresponds to variant rs627928 [ dbSNP | Ensembl ].

VAR_012057

Natural variant

592

1

R → H. Ref.15
Corresponds to variant rs35896902 [ dbSNP | Ensembl ].

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.8

Mutagenesis

583

1

H → A: No change in enzymatic activity. Ref.9

Mutagenesis

584

1

P → A: No change in enzymatic activity. Ref.9

Mutagenesis

632

1

W → A: No change in enzymatic activity. Ref.9

Mutagenesis

661

1

D → A: Complete loss of enzymatic activity. Ref.9

Mutagenesis

667

1

R → A: Complete loss of enzymatic activity. No change in 2-5A binding and enzyme dimerization. Ref.9

Mutagenesis

672

1

H → A: Complete loss of enzymatic activity. No change in 2-5A binding activity and enzyme dimerization. Ref.9

Secondary structure

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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 [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]	"Cloning and characterization of a RNase L inhibitor. A new component of the interferon-regulated 2-5A pathway." Bisbal C., Martinand C., Silhol M., Lebleu B., Salehzada T. J. Biol. Chem. 270:13308-13317(1995) [PubMed: 7539425] [Abstract] Cited for: INTERACTION WITH ABCE1.
[5]	"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.
[6]	Erratum Le Roy F., Bisbal C., Silhol M., Martinand C., Lebleu B., Salehzada T. J. Biol. Chem. 277:13354-13354(2002)
[7]	"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.
[8]	"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.
[9]	"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.
[10]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed: 19608861] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-684, MASS SPECTROMETRY.
[11]	"Structural basis for recognition of 2',5'-linked oligoadenylates by human ribonuclease L." Tanaka N., Nakanishi M., Kusakabe Y., Goto Y., Kitade Y., Nakamura K.T. EMBO J. 23:3929-3938(2004) [PubMed: 15385955] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 21-305 IN COMPLEX WITH THE ACTIVATOR 2-5A.
[12]	"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.
[13]	"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.
[14]	"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.
[15]	"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

EMBL
GenBank
DDBJ

L10381 Genomic DNA. Translation: AAA18032.1.

IPI

IPI00015864.

PIR

A45771.

RefSeq

NP_066956.1. NM_021133.3.

UniGene

Hs.518545.

3D structure databases

PDBe
RCSB PDB
PDBj

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

ProteinModelPortal

Q05823.

SMR

Q05823. Positions 21-332, 357-722.

ModBase

Search...

Protein-protein interaction databases

STRING

Q05823.

PTM databases

PhosphoSite

Q05823.

Polymorphism databases

DMDM

1350802.

Proteomic databases

PeptideAtlas

Q05823.

PRIDE

Q05823.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000367559; ENSP00000356530; ENSG00000135828.
ENST00000444138; ENSP00000411147; ENSG00000135828.

GeneID

6041.

KEGG

hsa:6041.

UCSC

uc001gpj.1. human.

Organism-specific databases

CTD

6041.

GeneCards

GC01M182542.

H-InvDB

HIX0028845.

HGNC

HGNC:10050. RNASEL.

HPA

CAB010906.
HPA002633.

MIM

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

neXtProt

NX_Q05823.

Orphanet

1331. Familial prostate cancer.

PharmGKB

PA34418.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG04117.

HOGENOM

HBG280468.

HOVERGEN

HBG012673.

InParanoid

Q05823.

OMA

NMGRNAL.

OrthoDB

EOG479F6R.

PhylomeDB

Q05823.

Enzyme and pathway databases

Reactome

REACT_6900. Immune System.

Gene expression databases

ArrayExpress

Q05823.

Bgee

Q05823.

CleanEx

HS_RNASEL.

Genevestigator

Q05823.

GermOnline

ENSG00000135828. Homo sapiens.

Family and domain databases

InterPro

IPR002110. Ankyrin_rpt.
IPR020683. Ankyrin_rpt-contain_dom.
IPR010513. KEN_RNase_activator.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_dom.
IPR006567. PUG-dom.
IPR017442. Se/Thr_kinase-like_dom.
[Graphical view]

Gene3D

G3DSA:1.25.40.20. ANK. 1 hit.

KO

K01165.

Pfam

PF00023. Ank. 4 hits.
PF12796. Ank_2. 1 hit.
PF00069. Pkinase. 1 hit.
PF06479. Ribonuc_2-5A. 1 hit.
[Graphical view]

PRINTS

PR01415. ANKYRIN.

SMART

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

SUPFAM

SSF48403. ANK. 1 hit.
SSF56112. Kinase_like. 1 hit.

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

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:	January 25, 2012
This is version 114 of the entry and version 2 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.