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 13-FEB-2019, entry version 187. 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; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; 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 RT in situ and immunocytochemistry."; RL Biochem. J. 278:627-635(1991). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=1334620; 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 RT epithelial cell populations during the evolution of type 2 cystatin RT 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., RA Beasley O.P., Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J., RA Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P., RA Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M., RA Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R., RA Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M., RA 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., RA Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., RA Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E., RA Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., RA Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M., RA Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A., RA Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., RA 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 RT project: 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 RT phosphoproteins 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., RA Nancollas G.H.; RT "The effects of human salivary cystatins and statherin on RT hydroxyapatite crystallization."; RL Arch. Oral Biol. 36:631-636(1991). RN [10] RP PROTEIN SEQUENCE OF 29-141. RX PubMed=6501254; RA Isemura S., Saitoh E., Sanada K.; RT "Isolation and amino acid sequence of SAP-1, an acidic protein of RT human 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 RT followed 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 RT enamel pellicle, is phosphorylated at both its amino- and carboxyl- RT terminal regions."; RL Arch. Biochem. Biophys. 288:664-670(1991). RN [14] RP PHOSPHORYLATION AT SER-21 AND SER-23, DISULFIDE BONDS, TISSUE RP SPECIFICITY, 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 RT using top-down Fourier-transform ion cyclotron resonance mass RT 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., RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C., RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., RA Vogelstein B., Kinzler K.W., Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal RT cancers."; RL Science 314:268-274(2006). CC -!- FUNCTION: This protein strongly inhibits papain and ficin, CC partially inhibits stem bromelain and bovine cathepsin C, but does CC not inhibit porcine cathepsin B or clostripain. Papain is CC inhibited non-competitively. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:20189825}. CC -!- TISSUE SPECIFICITY: Expressed in submandibular and sublingual CC saliva but not in parotid saliva (at protein level). Expressed in CC saliva, tears, urine and seminal fluid. CC {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=14175.8569; Mass_error=0.0564; CC Method=Electrospray; Range=21-141; CC Evidence={ECO:0000269|PubMed:20189825}; CC -!- MASS SPECTROMETRY: Mass=14255.8567; Mass_error=0.0899; CC Method=Electrospray; Range=21-141; Note=Monophosphorylated at Ser- CC 23, also called form S1.; Evidence={ECO:0000269|PubMed:20189825}; CC -!- MASS SPECTROMETRY: Mass=14335.811; Mass_error=0.0775; CC Method=Electrospray; Range=21-141; Note=Diphosphorylated at Ser-21 CC and Ser-23, also called form S2.; CC Evidence={ECO:0000269|PubMed:20189825}; CC -!- SIMILARITY: Belongs to the cystatin family. {ECO:0000305}. CC ----------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC ----------------------------------------------------------------------- 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 UniGene; Hs.654549; -. DR ProteinModelPortal; P01036; -. DR SMR; P01036; -. DR BioGrid; 107854; 50. DR IntAct; P01036; 2. 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 MaxQB; P01036; -. DR PaxDb; P01036; -. DR PeptideAtlas; P01036; -. DR PRIDE; P01036; -. DR ProteomicsDB; 51312; -. DR TopDownProteomics; P01036; -. DR DNASU; 1472; -. DR Ensembl; ENST00000217423; ENSP00000217423; ENSG00000101441. DR GeneID; 1472; -. DR KEGG; hsa:1472; -. DR UCSC; uc002wto.2; human. DR CTD; 1472; -. DR DisGeNET; 1472; -. DR EuPathDB; HostDB:ENSG00000101441.4; -. DR GeneCards; CST4; -. DR HGNC; HGNC:2476; CST4. DR HPA; HPA043706; -. DR HPA; HPA044763; -. DR MIM; 123857; gene. DR neXtProt; NX_P01036; -. DR OpenTargets; ENSG00000101441; -. DR PharmGKB; PA26977; -. DR eggNOG; ENOG410IZZH; Eukaryota. DR eggNOG; ENOG4112CFJ; LUCA. DR GeneTree; ENSGT00940000163410; -. DR HOGENOM; HOG000231754; -. DR HOVERGEN; HBG009556; -. DR InParanoid; P01036; -. DR KO; K13900; -. DR OMA; DIARTEC; -. DR OrthoDB; 1565344at2759; -. DR PhylomeDB; P01036; -. DR ChiTaRS; CST4; human. DR GeneWiki; CST4; -. DR GenomeRNAi; 1472; -. DR PRO; PR:P01036; -. DR Proteomes; UP000005640; Chromosome 20. DR Bgee; ENSG00000101441; Expressed in 120 organ(s), highest expression level in saliva-secreting gland. DR Genevisible; P01036; HS. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB. 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 GO; GO:0001895; P:retina homeostasis; HEP:UniProtKB. DR CDD; cd00042; CY; 1. DR InterPro; IPR027214; Cystatin. DR InterPro; IPR000010; Cystatin_dom. DR InterPro; IPR018073; Prot_inh_cystat_CS. DR PANTHER; PTHR11413; PTHR11413; 1. DR Pfam; PF00031; Cystatin; 1. DR SMART; SM00043; CY; 1. DR PROSITE; PS00287; CYSTATIN; 1. PE 1: Evidence at protein level; KW Complete proteome; Direct protein sequencing; Disulfide bond; KW Phosphoprotein; Polymorphism; Protease inhibitor; Reference proteome; KW Secreted; Signal; Thiol protease inhibitor. FT SIGNAL 1 20 {ECO:0000269|PubMed:1741693, FT ECO:0000269|PubMed:1747107, FT ECO:0000269|PubMed:1778989, FT ECO:0000269|PubMed:3496880}. FT CHAIN 21 141 Cystatin-S. FT /FTId=PRO_0000006650. FT MOTIF 76 80 Secondary area of contact. FT SITE 32 32 Reactive site. FT MOD_RES 21 21 Phosphoserine. FT {ECO:0000269|PubMed:1778989, FT ECO:0000269|PubMed:20189825}. FT MOD_RES 23 23 Phosphoserine. FT {ECO:0000269|PubMed:1741693, FT ECO:0000269|PubMed:1747107, FT ECO:0000269|PubMed:1778989, FT ECO:0000269|PubMed:20189825}. FT DISULFID 94 104 {ECO:0000250}. FT DISULFID 118 138 {ECO:0000250}. FT VARIANT 36 36 D -> N (in dbSNP:rs3210291). FT /FTId=VAR_048852. FT VARIANT 77 77 T -> N (in a breast cancer sample; FT somatic mutation). FT {ECO:0000269|PubMed:16959974}. FT /FTId=VAR_036549. FT CONFLICT 135 135 N -> D (in Ref. 10; AA sequence). FT {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 //