ID   CYTS_HUMAN              Reviewed;         141 AA.
AC   P01036; Q9UBI5; Q9UCS9;
DT   21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT   01-JUL-1993, sequence version 3.
DT   24-JAN-2024, entry version 212.
DE   RecName: Full=Cystatin-S;
DE   AltName: Full=Cystatin-4;
DE   AltName: Full=Cystatin-SA-III;
DE   AltName: Full=Salivary acidic protein 1;
DE   Flags: Precursor;
GN   Name=CST4;
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=Submandibular gland;
RX   PubMed=1898352; DOI=10.1042/bj2780627;
RA   Bobek L.A., Aguirre A., Levine M.J.;
RT   "Human salivary cystatin S. Cloning, sequence analysis, hybridization in
RT   situ and immunocytochemistry.";
RL   Biochem. J. 278:627-635(1991).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=1334620; DOI=10.1007/978-3-0348-7321-5_43;
RA   Saitoh E., Isemura S., Sanada K., Ohnishi K.;
RT   "Characterization of two members (CST4 and CST5) of the cystatin gene
RT   family and molecular evolution of cystatin genes.";
RL   Agents Actions 38:340-348(1992).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA   Dickinson D.P., Hewett-Emmett D., Thiesse M.;
RT   "Acquisition of complex patterns of differential expression in epithelial
RT   cell populations during the evolution of type 2 cystatin genes.";
RL   Submitted (NOV-2000) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=11780052; DOI=10.1038/414865a;
RA   Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R.,
RA   Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L.,
RA   Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P.,
RA   Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J., Buck D., Burrill W.D.,
RA   Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G.,
RA   Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E.,
RA   Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D.,
RA   Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P.,
RA   Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E.,
RA   Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J.,
RA   Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D.,
RA   Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S.,
RA   Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D.,
RA   Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A.,
RA   Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T.,
RA   Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I.,
RA   Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M.,
RA   Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D.,
RA   Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M.,
RA   Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A.,
RA   Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L.,
RA   Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L.,
RA   Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.;
RT   "The DNA sequence and comparative analysis of human chromosome 20.";
RL   Nature 414:865-871(2001).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Thyroid;
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   [6]
RP   PROTEIN SEQUENCE OF 21-51.
RX   PubMed=3496880; DOI=10.1016/0006-291x(87)91571-3;
RA   Hawke D.H., Yuan P.M., Wilson K.J., Hunkapiller M.W.;
RT   "Identification of a long form of cystatin from human saliva by rapid
RT   microbore HPLC mapping.";
RL   Biochem. Biophys. Res. Commun. 145:1248-1253(1987).
RN   [7]
RP   PROTEIN SEQUENCE OF 21-55, AND PHOSPHORYLATION AT SER-23.
RC   TISSUE=Saliva;
RX   PubMed=1747107; DOI=10.1042/bj2800341;
RA   Ramasubbu N., Reddy M.S., Bergey E.J., Haraszthy G.G., Soni S.-D.,
RA   Levine M.J.;
RT   "Large-scale purification and characterization of the major phosphoproteins
RT   and mucins of human submandibular-sublingual saliva.";
RL   Biochem. J. 280:341-352(1991).
RN   [8]
RP   PROTEIN SEQUENCE OF 21-36, AND PHOSPHORYLATION AT SER-21 AND SER-23.
RC   TISSUE=Saliva;
RX   PubMed=1778989; DOI=10.1093/oxfordjournals.jbchem.a123634;
RA   Isemura S., Saitoh E., Sanada K., Minakata K.;
RT   "Identification of full-sized forms of salivary (S-type) cystatins
RT   (cystatin SN, cystatin SA, cystatin S, and two phosphorylated forms of
RT   cystatin S) in human whole saliva and determination of phosphorylation
RT   sites of cystatin S.";
RL   J. Biochem. 110:648-654(1991).
RN   [9]
RP   PROTEIN SEQUENCE OF 21-36, AND PHOSPHORYLATION AT SER-23.
RC   TISSUE=Saliva;
RX   PubMed=1741693; DOI=10.1016/0003-9969(91)90014-l;
RA   Johnsson M., Richardson C.F., Bergey E.J., Levine M.J., Nancollas G.H.;
RT   "The effects of human salivary cystatins and statherin on hydroxyapatite
RT   crystallization.";
RL   Arch. Oral Biol. 36:631-636(1991).
RN   [10]
RP   PROTEIN SEQUENCE OF 29-141.
RX   PubMed=6501254; DOI=10.1093/oxfordjournals.jbchem.a134861;
RA   Isemura S., Saitoh E., Sanada K.;
RT   "Isolation and amino acid sequence of SAP-1, an acidic protein of human
RT   whole saliva, and sequence homology with human gamma-trace.";
RL   J. Biochem. 96:489-498(1984).
RN   [11]
RP   PROTEIN SEQUENCE OF 85-141, AND IDENTIFICATION BY MASS SPECTROMETRY.
RC   TISSUE=Tear;
RX   PubMed=25946035; DOI=10.1021/acs.jproteome.5b00179;
RA   Azkargorta M., Soria J., Ojeda C., Guzman F., Acera A., Iloro I.,
RA   Suarez T., Elortza F.;
RT   "Human basal tear peptidome characterization by CID, HCD, and ETD followed
RT   by in silico and in vitro analyses for antimicrobial peptide
RT   identification.";
RL   J. Proteome Res. 14:2649-2658(2015).
RN   [12]
RP   INHIBITOR SPECIFICITY.
RX   PubMed=6394600; DOI=10.1093/oxfordjournals.jbchem.a134952;
RA   Isemura S., Saitoh E., Ito S., Isemura M., Sanada K.;
RT   "Cystatin S: a cysteine proteinase inhibitor of human saliva.";
RL   J. Biochem. 96:1311-1314(1984).
RN   [13]
RP   PHOSPHORYLATION.
RX   PubMed=1898055; DOI=10.1016/0003-9861(91)90249-i;
RA   Lamkin M.S., Jensen J.L., Setayesh M.R., Troxler R.F., Oppenheim F.G.;
RT   "Salivary cystatin SA-III, a potential precursor of the acquired enamel
RT   pellicle, is phosphorylated at both its amino- and carboxyl-terminal
RT   regions.";
RL   Arch. Biochem. Biophys. 288:664-670(1991).
RN   [14]
RP   PHOSPHORYLATION AT SER-21 AND SER-23, DISULFIDE BONDS, TISSUE SPECIFICITY,
RP   SUBCELLULAR LOCATION, AND MASS SPECTROMETRY.
RC   TISSUE=Saliva;
RX   PubMed=20189825; DOI=10.1016/j.jasms.2010.01.025;
RA   Ryan C.M., Souda P., Halgand F., Wong D.T., Loo J.A., Faull K.F.,
RA   Whitelegge J.P.;
RT   "Confident assignment of intact mass tags to human salivary cystatins using
RT   top-down Fourier-transform ion cyclotron resonance mass spectrometry.";
RL   J. Am. Soc. Mass Spectrom. 21:908-917(2010).
RN   [15]
RP   VARIANT [LARGE SCALE ANALYSIS] ASN-77.
RX   PubMed=16959974; DOI=10.1126/science.1133427;
RA   Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA   Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA   Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA   Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA   Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA   Velculescu V.E.;
RT   "The consensus coding sequences of human breast and colorectal cancers.";
RL   Science 314:268-274(2006).
CC   -!- FUNCTION: This protein strongly inhibits papain and ficin, partially
CC       inhibits stem bromelain and bovine cathepsin C, but does not inhibit
CC       porcine cathepsin B or clostripain. Papain is inhibited non-
CC       competitively.
CC   -!- INTERACTION:
CC       P01036; Q9UHD9: UBQLN2; NbExp=3; IntAct=EBI-1049999, EBI-947187;
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:20189825}.
CC   -!- TISSUE SPECIFICITY: Expressed in submandibular and sublingual saliva
CC       but not in parotid saliva (at protein level). Expressed in saliva,
CC       tears, urine and seminal fluid. {ECO:0000269|PubMed:20189825}.
CC   -!- PTM: Phosphorylated at both its N- and C-terminal regions.
CC       {ECO:0000269|PubMed:1741693, ECO:0000269|PubMed:1747107,
CC       ECO:0000269|PubMed:1778989, ECO:0000269|PubMed:1898055,
CC       ECO:0000269|PubMed:20189825}.
CC   -!- MASS SPECTROMETRY: Mass=14175.856; Mass_error=0.0564;
CC       Method=Electrospray; Evidence={ECO:0000269|PubMed:20189825};
CC   -!- MASS SPECTROMETRY: Mass=14255.856; Mass_error=0.0899;
CC       Method=Electrospray; Note=Monophosphorylated at Ser-23, also called
CC       form S1.; Evidence={ECO:0000269|PubMed:20189825};
CC   -!- MASS SPECTROMETRY: Mass=14335.811; Mass_error=0.0775;
CC       Method=Electrospray; Note=Diphosphorylated at Ser-21 and Ser-23, also
CC       called form S2.; Evidence={ECO:0000269|PubMed:20189825};
CC   -!- SIMILARITY: Belongs to the cystatin family. {ECO:0000305}.
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DR   EMBL; X54667; CAA38478.1; -; mRNA.
DR   EMBL; S51222; AAB24493.1; -; Genomic_DNA.
DR   EMBL; S51214; AAB24493.1; JOINED; Genomic_DNA.
DR   EMBL; S51219; AAB24493.1; JOINED; Genomic_DNA.
DR   EMBL; AF319565; AAK11571.1; -; Genomic_DNA.
DR   EMBL; AL359433; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC065714; AAH65714.1; -; mRNA.
DR   EMBL; BC074952; AAH74952.1; -; mRNA.
DR   EMBL; BC074953; AAH74953.1; -; mRNA.
DR   CCDS; CCDS13159.1; -.
DR   PIR; S17667; UDHUP1.
DR   RefSeq; NP_001890.1; NM_001899.2.
DR   AlphaFoldDB; P01036; -.
DR   SMR; P01036; -.
DR   BioGRID; 107854; 109.
DR   IntAct; P01036; 34.
DR   STRING; 9606.ENSP00000217423; -.
DR   MEROPS; I25.008; -.
DR   iPTMnet; P01036; -.
DR   PhosphoSitePlus; P01036; -.
DR   SwissPalm; P01036; -.
DR   BioMuta; CST4; -.
DR   DMDM; 399336; -.
DR   jPOST; P01036; -.
DR   MassIVE; P01036; -.
DR   MaxQB; P01036; -.
DR   PaxDb; 9606-ENSP00000217423; -.
DR   PeptideAtlas; P01036; -.
DR   PRIDE; P01036; -.
DR   ProteomicsDB; 51312; -.
DR   TopDownProteomics; P01036; -.
DR   Antibodypedia; 9816; 380 antibodies from 27 providers.
DR   DNASU; 1472; -.
DR   Ensembl; ENST00000217423.4; ENSP00000217423.3; ENSG00000101441.5.
DR   GeneID; 1472; -.
DR   KEGG; hsa:1472; -.
DR   MANE-Select; ENST00000217423.4; ENSP00000217423.3; NM_001899.3; NP_001890.1.
DR   UCSC; uc002wto.2; human.
DR   AGR; HGNC:2476; -.
DR   CTD; 1472; -.
DR   DisGeNET; 1472; -.
DR   GeneCards; CST4; -.
DR   HGNC; HGNC:2476; CST4.
DR   HPA; ENSG00000101441; Tissue enriched (salivary).
DR   MIM; 123857; gene.
DR   neXtProt; NX_P01036; -.
DR   OpenTargets; ENSG00000101441; -.
DR   PharmGKB; PA26977; -.
DR   VEuPathDB; HostDB:ENSG00000101441; -.
DR   eggNOG; ENOG502SC50; Eukaryota.
DR   GeneTree; ENSGT00940000163410; -.
DR   HOGENOM; CLU_118168_0_1_1; -.
DR   InParanoid; P01036; -.
DR   OMA; PWEDKMS; -.
DR   OrthoDB; 3086783at2759; -.
DR   PhylomeDB; P01036; -.
DR   PathwayCommons; P01036; -.
DR   SignaLink; P01036; -.
DR   BioGRID-ORCS; 1472; 20 hits in 1112 CRISPR screens.
DR   ChiTaRS; CST4; human.
DR   GeneWiki; CST4; -.
DR   GenomeRNAi; 1472; -.
DR   Pharos; P01036; Tbio.
DR   PRO; PR:P01036; -.
DR   Proteomes; UP000005640; Chromosome 20.
DR   RNAct; P01036; Protein.
DR   Bgee; ENSG00000101441; Expressed in parotid gland and 57 other cell types or tissues.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR   GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR   GO; GO:0031982; C:vesicle; IBA:GO_Central.
DR   GO; GO:0004869; F:cysteine-type endopeptidase inhibitor activity; IDA:UniProtKB.
DR   GO; GO:0001580; P:detection of chemical stimulus involved in sensory perception of bitter taste; IDA:UniProtKB.
DR   GO; GO:0045861; P:negative regulation of proteolysis; IDA:UniProtKB.
DR   CDD; cd00042; CY; 1.
DR   Gene3D; 3.10.450.10; -; 1.
DR   InterPro; IPR000010; Cystatin_dom.
DR   InterPro; IPR046350; Cystatin_sf.
DR   InterPro; IPR018073; Prot_inh_cystat_CS.
DR   PANTHER; PTHR46186; CYSTATIN; 1.
DR   PANTHER; PTHR46186:SF3; CYSTATIN-S-RELATED; 1.
DR   Pfam; PF00031; Cystatin; 1.
DR   SMART; SM00043; CY; 1.
DR   SUPFAM; SSF54403; Cystatin/monellin; 1.
DR   PROSITE; PS00287; CYSTATIN; 1.
DR   Genevisible; P01036; HS.
PE   1: Evidence at protein level;
KW   Direct protein sequencing; Disulfide bond; Phosphoprotein;
KW   Protease inhibitor; Reference proteome; Secreted; Signal;
KW   Thiol protease inhibitor.
FT   SIGNAL          1..20
FT                   /evidence="ECO:0000269|PubMed:1741693,
FT                   ECO:0000269|PubMed:1747107, ECO:0000269|PubMed:1778989,
FT                   ECO:0000269|PubMed:3496880"
FT   CHAIN           21..141
FT                   /note="Cystatin-S"
FT                   /id="PRO_0000006650"
FT   MOTIF           76..80
FT                   /note="Secondary area of contact"
FT   SITE            32
FT                   /note="Reactive site"
FT   MOD_RES         21
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:1778989,
FT                   ECO:0000269|PubMed:20189825"
FT   MOD_RES         23
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:1741693,
FT                   ECO:0000269|PubMed:1747107, ECO:0000269|PubMed:1778989,
FT                   ECO:0000269|PubMed:20189825"
FT   DISULFID        94..104
FT                   /evidence="ECO:0000250"
FT   DISULFID        118..138
FT                   /evidence="ECO:0000250"
FT   VARIANT         36
FT                   /note="D -> N (in dbSNP:rs3210291)"
FT                   /id="VAR_048852"
FT   VARIANT         77
FT                   /note="T -> N (in a breast cancer sample; somatic
FT                   mutation)"
FT                   /evidence="ECO:0000269|PubMed:16959974"
FT                   /id="VAR_036549"
FT   CONFLICT        135
FT                   /note="N -> D (in Ref. 10; AA sequence)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   141 AA;  16214 MW;  65B1FEB8F074DEA6 CRC64;
     MARPLCTLLL LMATLAGALA SSSKEENRII PGGIYDADLN DEWVQRALHF AISEYNKATE
     DEYYRRPLQV LRAREQTFGG VNYFFDVEVG RTICTKSQPN LDTCAFHEQP ELQKKQLCSF
     EIYEVPWEDR MSLVNSRCQE A
//