ID   RNAS4_HUMAN             Reviewed;         147 AA.
AC   P34096;
DT   01-FEB-1994, integrated into UniProtKB/Swiss-Prot.
DT   01-OCT-1996, sequence version 3.
DT   02-SEP-2026, entry version 208.
DE   RecName: Full=Ribonuclease 4;
DE            Short=RNase 4;
DE            EC=3.1.27.- {ECO:0000269|PubMed:3467790};
DE   Flags: Precursor;
GN   Name=RNASE4; Synonyms=RNS4;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Pancreas;
RX   PubMed=7742370; DOI=10.1016/0167-4781(95)00040-n;
RA   Seno M., Futami J., Tsushima Y., Akutagawa K., Kosaka M., Tada H.,
RA   Yamada H.;
RT   "Molecular cloning and expression of human ribonuclease 4 cDNA.";
RL   Biochim. Biophys. Acta 1261:424-426(1995).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Pancreas;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 29-147.
RX   PubMed=7501448; DOI=10.1093/nar/23.21.4290;
RA   Rosenberg H.F., Dyer K.D.;
RT   "Human ribonuclease 4 (RNase 4): coding sequence, chromosomal localization
RT   and identification of two distinct transcripts in human somatic tissues.";
RL   Nucleic Acids Res. 23:4290-4295(1995).
RN   [4]
RP   PROTEIN SEQUENCE OF 29-147, PYROGLUTAMATE FORMATION AT GLN-29, AND
RP   DISULFIDE BONDS.
RC   TISSUE=Plasma;
RX   PubMed=8223579; DOI=10.1111/j.1432-1033.1993.tb18259.x;
RA   Zhou H.-M., Strydom D.J.;
RT   "The amino acid sequence of human ribonuclease 4, a highly conserved
RT   ribonuclease that cleaves specifically on the 3' side of uridine.";
RL   Eur. J. Biochem. 217:401-410(1993).
RN   [5]
RP   FUNCTION, AND CATALYTIC ACTIVITY.
RX   PubMed=3467790; DOI=10.1021/bi00371a002;
RA   Shapiro R., Fett J.W., Strydom D.J., Vallee B.L.;
RT   "Isolation and characterization of a human colon carcinoma-secreted enzyme
RT   with pancreatic ribonuclease-like activity.";
RL   Biochemistry 25:7255-7264(1986).
RN   [6]
RP   TISSUE SPECIFICITY, AND INDUCTION.
RX   PubMed=30418175; DOI=10.1172/jci98595;
RA   Murtha M.J., Eichler T., Bender K., Metheny J., Li B., Schwaderer A.L.,
RA   Mosquera C., James C., Schwartz L., Becknell B., Spencer J.D.;
RT   "Insulin receptor signaling regulates renal collecting duct and
RT   intercalated cell antibacterial defenses.";
RL   J. Clin. Invest. 128:5634-5646(2018).
RN   [7]
RP   FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX   PubMed=33818125; DOI=10.1152/ajprenal.00592.2020;
RA   Bender K., Schwartz L.L., Cohen A., Vasquez C.M., Murtha M.J., Eichler T.,
RA   Thomas J.P., Jackson A., Spencer J.D.;
RT   "Expression and function of human ribonuclease 4 in the kidney and urinary
RT   tract.";
RL   Am. J. Physiol. 320:F972-F983(2021).
RN   [8]
RP   X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 29-147.
RX   PubMed=9878400; DOI=10.1006/jmbi.1998.2288;
RA   Terzyan S.S., Peracaula R., de Llorens R., Tsushima Y., Yamada H., Seno M.,
RA   Gomis-Rueth F.-X., Coll M.;
RT   "The three-dimensional structure of human RNase 4, unliganded and complexed
RT   with d(Up), reveals the basis for its uridine selectivity.";
RL   J. Mol. Biol. 285:205-214(1999).
CC   -!- FUNCTION: Cleaves preferentially after uridine bases (PubMed:3467790).
CC       Has antimicrobial activity against uropathogenic E.coli (UPEC)
CC       (PubMed:33818125). Probably contributes to urinary tract sterility
CC       (PubMed:33818125). {ECO:0000269|PubMed:33818125,
CC       ECO:0000269|PubMed:3467790}.
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:33818125}.
CC       Note=Detected in urine. {ECO:0000269|PubMed:33818125}.
CC   -!- TISSUE SPECIFICITY: Expressed in the cortical and medullary tubules of
CC       the kidney, and in the transitional epithelium of the urinary bladder
CC       (at protein level). {ECO:0000269|PubMed:30418175,
CC       ECO:0000269|PubMed:33818125}.
CC   -!- INDUCTION: Induced in response to insulin.
CC       {ECO:0000269|PubMed:30418175}.
CC   -!- SIMILARITY: Belongs to the pancreatic ribonuclease family.
CC       {ECO:0000305}.
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DR   EMBL; D37931; BAA07150.1; -; mRNA.
DR   EMBL; BC015520; AAH15520.1; -; mRNA.
DR   EMBL; U36775; AAA96750.1; -; Genomic_DNA.
DR   CCDS; CCDS9555.1; -.
DR   PIR; I52489; I52489.
DR   RefSeq; NP_001269121.1; NM_001282192.2.
DR   RefSeq; NP_001269122.1; NM_001282193.2.
DR   RefSeq; NP_002928.1; NM_002937.5.
DR   RefSeq; NP_919412.1; NM_194431.3.
DR   PDB; 1RNF; X-ray; 2.10 A; A/B=29-147.
DR   PDB; 2RNF; X-ray; 2.40 A; A/B=29-147.
DR   AlphaFoldDB; P34096; -.
DR   SMR; P34096; -.
DR   BioGRID; 111967; 14.
DR   FunCoup; P34096; 448.
DR   IntAct; P34096; 15.
DR   STRING; 9606.ENSP00000452245; -.
DR   DrugBank; DB03448; 2'-Deoxyuridine 3'-Monophosphate.
DR   BioMuta; RNASE4; -.
DR   DMDM; 1710614; -.
DR   jPOST; P34096; -.
DR   MassIVE; P34096; -.
DR   PaxDb; 9606-ENSP00000452245; -.
DR   PeptideAtlas; P34096; -.
DR   PRIDE; P34096; -.
DR   ProteomicsDB; 54939; -.
DR   Pumba; P34096; -.
DR   Antibodypedia; 57712; 77 antibodies from 17 providers.
DR   DNASU; 6038; -.
DR   Ensembl; ENST00000397995.2; ENSP00000381081.2; ENSG00000258818.5.
DR   Ensembl; ENST00000555597.1; ENSP00000451624.1; ENSG00000258818.5.
DR   Ensembl; ENST00000555835.3; ENSP00000452245.1; ENSG00000258818.5.
DR   Ensembl; ENST00000885366.1; ENSP00000555425.1; ENSG00000258818.5.
DR   Ensembl; ENST00000885367.1; ENSP00000555426.1; ENSG00000258818.5.
DR   Ensembl; ENST00000885368.1; ENSP00000555427.1; ENSG00000258818.5.
DR   Ensembl; ENST00000885369.1; ENSP00000555428.1; ENSG00000258818.5.
DR   Ensembl; ENST00000885370.1; ENSP00000555429.1; ENSG00000258818.5.
DR   Ensembl; ENST00000885371.1; ENSP00000555430.1; ENSG00000258818.5.
DR   Ensembl; ENST00000885372.1; ENSP00000555431.1; ENSG00000258818.5.
DR   Ensembl; ENST00000885373.1; ENSP00000555432.1; ENSG00000258818.5.
DR   Ensembl; ENST00000885374.1; ENSP00000555433.1; ENSG00000258818.5.
DR   Ensembl; ENST00000885375.1; ENSP00000555434.1; ENSG00000258818.5.
DR   Ensembl; ENST00000885376.1; ENSP00000555435.1; ENSG00000258818.5.
DR   Ensembl; ENST00000885377.1; ENSP00000555436.1; ENSG00000258818.5.
DR   Ensembl; ENST00000885378.1; ENSP00000555437.1; ENSG00000258818.5.
DR   Ensembl; ENST00000885379.1; ENSP00000555438.1; ENSG00000258818.5.
DR   Ensembl; ENST00000971275.1; ENSP00000641334.1; ENSG00000258818.5.
DR   Ensembl; ENST00000971276.1; ENSP00000641335.1; ENSG00000258818.5.
DR   GeneID; 6038; -.
DR   KEGG; hsa:6038; -.
DR   MANE-Select; ENST00000555835.3; ENSP00000452245.1; NM_002937.5; NP_002928.1.
DR   AGR; HGNC:10047; -.
DR   ClinPGx; PA34415; -.
DR   CTD; 6038; -.
DR   DisGeNET; 6038; -.
DR   GeneCards; RNASE4; -.
DR   HGNC; HGNC:10047; RNASE4.
DR   HPA; ENSG00000258818; Tissue enriched (liver).
DR   MalaCards; RNASE4; -.
DR   MIM; 601030; gene.
DR   OpenTargets; ENSG00000258818; -.
DR   VEuPathDB; HostDB:ENSG00000258818; -.
DR   eggNOG; ENOG502S9Q1; Eukaryota.
DR   GeneTree; ENSGT00940000157645; -.
DR   HOGENOM; CLU_117006_3_1_1; -.
DR   InParanoid; P34096; -.
DR   OMA; ATSHHCK; -.
DR   OrthoDB; 8573660at2759; -.
DR   PAN-GO; P34096; 3 GO annotations based on evolutionary models.
DR   PhylomeDB; P34096; -.
DR   PathwayCommons; P34096; -.
DR   SignaLink; P34096; -.
DR   Agora; ENSG00000258818; -.
DR   BioGRID-ORCS; 6038; 12 hits in 1140 CRISPR screens.
DR   ChiTaRS; RNASE4; human.
DR   EvolutionaryTrace; P34096; -.
DR   GeneWiki; Ribonuclease_4; -.
DR   GenomeRNAi; 6038; -.
DR   Pharos; P34096; Tbio.
DR   PRO; PR:P34096; -.
DR   Proteomes; UP000005640; Chromosome 14.
DR   RNAct; P34096; protein.
DR   Bgee; ENSG00000258818; Expressed in right lobe of liver and 94 other cell types or tissues.
DR   ExpressionAtlas; P34096; baseline and differential.
DR   GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
DR   GO; GO:0003676; F:nucleic acid binding; IEA:InterPro.
DR   GO; GO:0004522; F:ribonuclease A activity; NAS:UniProtKB.
DR   GO; GO:0004540; F:RNA nuclease activity; IDA:BHF-UCL.
DR   GO; GO:0019731; P:antibacterial humoral response; IMP:UniProtKB.
DR   GO; GO:0050830; P:defense response to Gram-positive bacterium; IBA:GO_Central.
DR   CDD; cd06265; RNase_A_canonical; 1.
DR   FunFam; 3.10.130.10:FF:000001; Ribonuclease pancreatic; 1.
DR   Gene3D; 3.10.130.10; Ribonuclease A-like domain; 1.
DR   InterPro; IPR001427; RNaseA.
DR   InterPro; IPR036816; RNaseA-like_dom_sf.
DR   InterPro; IPR023411; RNaseA_AS.
DR   InterPro; IPR023412; RNaseA_domain.
DR   PANTHER; PTHR11437; RIBONUCLEASE; 1.
DR   PANTHER; PTHR11437:SF53; RIBONUCLEASE 4; 1.
DR   Pfam; PF00074; RnaseA; 1.
DR   PRINTS; PR00794; RIBONUCLEASE.
DR   SMART; SM00092; RNAse_Pc; 1.
DR   SUPFAM; SSF54076; RNase A-like; 1.
DR   PROSITE; PS00127; RNASE_PANCREATIC; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Antibiotic; Antimicrobial; Direct protein sequencing;
KW   Disulfide bond; Endonuclease; Hydrolase; Nuclease;
KW   Proteomics identification; Pyrrolidone carboxylic acid; Reference proteome;
KW   Secreted; Signal.
FT   SIGNAL          1..28
FT                   /evidence="ECO:0000269|PubMed:8223579"
FT   CHAIN           29..147
FT                   /note="Ribonuclease 4"
FT                   /id="PRO_0000030883"
FT   ACT_SITE        40
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000250|UniProtKB:Q9H1E1"
FT   ACT_SITE        144
FT                   /note="Proton donor"
FT                   /evidence="ECO:0000250|UniProtKB:Q9H1E1"
FT   BINDING         35
FT                   /ligand="dUMP"
FT                   /ligand_id="ChEBI:CHEBI:246422"
FT                   /evidence="ECO:0000250|UniProtKB:P15468"
FT   BINDING         40
FT                   /ligand="dUMP"
FT                   /ligand_id="ChEBI:CHEBI:246422"
FT                   /evidence="ECO:0000250|UniProtKB:P15468"
FT   BINDING         68
FT                   /ligand="dUMP"
FT                   /ligand_id="ChEBI:CHEBI:246422"
FT                   /evidence="ECO:0000250|UniProtKB:P15468"
FT   BINDING         71
FT                   /ligand="dUMP"
FT                   /ligand_id="ChEBI:CHEBI:246422"
FT                   /evidence="ECO:0000250|UniProtKB:P15468"
FT   BINDING         72
FT                   /ligand="dUMP"
FT                   /ligand_id="ChEBI:CHEBI:246422"
FT                   /evidence="ECO:0000250|UniProtKB:P15468"
FT   BINDING         145
FT                   /ligand="dUMP"
FT                   /ligand_id="ChEBI:CHEBI:246422"
FT                   /evidence="ECO:0000250|UniProtKB:P15468"
FT   MOD_RES         29
FT                   /note="Pyrrolidone carboxylic acid"
FT                   /evidence="ECO:0000269|PubMed:8223579"
FT   DISULFID        53..109
FT                   /evidence="ECO:0000269|PubMed:8223579"
FT   DISULFID        67..120
FT                   /evidence="ECO:0000269|PubMed:8223579"
FT   DISULFID        85..135
FT                   /evidence="ECO:0000269|PubMed:8223579"
FT   DISULFID        92..99
FT                   /evidence="ECO:0000269|PubMed:8223579"
FT   VARIANT         16
FT                   /note="T -> S (in dbSNP:rs3748338)"
FT                   /id="VAR_024618"
FT   CONFLICT        54
FT                   /note="N -> D (in Ref. 3; AAA96750)"
FT                   /evidence="ECO:0000305"
FT   HELIX           29..40
FT                   /evidence="ECO:0007829|PDB:1RNF"
FT   HELIX           50..59
FT                   /evidence="ECO:0007829|PDB:1RNF"
FT   STRAND          62..66
FT                   /evidence="ECO:0007829|PDB:1RNF"
FT   STRAND          69..74
FT                   /evidence="ECO:0007829|PDB:1RNF"
FT   HELIX           78..82
FT                   /evidence="ECO:0007829|PDB:1RNF"
FT   HELIX           83..86
FT                   /evidence="ECO:0007829|PDB:1RNF"
FT   STRAND          99..111
FT                   /evidence="ECO:0007829|PDB:1RNF"
FT   STRAND          113..115
FT                   /evidence="ECO:0007829|PDB:1RNF"
FT   STRAND          122..136
FT                   /evidence="ECO:0007829|PDB:1RNF"
FT   TURN            137..140
FT                   /evidence="ECO:0007829|PDB:1RNF"
FT   STRAND          141..145
FT                   /evidence="ECO:0007829|PDB:1RNF"
SQ   SEQUENCE   147 AA;  16840 MW;  4C24FEA249F3EC2F CRC64;
     MALQRTHSLL LLLLLTLLGL GLVQPSYGQD GMYQRFLRQH VHPEETGGSD RYCNLMMQRR
     KMTLYHCKRF NTFIHEDIWN IRSICSTTNI QCKNGKMNCH EGVVKVTDCR DTGSSRAPNC
     RYRAIASTRR VVIACEGNPQ VPVHFDG
//