CYTM_HUMAN
ID CYTM_HUMAN Reviewed; 149 AA.
AC Q15828; Q540N7;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1997, sequence version 1.
DT 03-AUG-2022, entry version 177.
DE RecName: Full=Cystatin-M;
DE AltName: Full=Cystatin-6;
DE AltName: Full=Cystatin-E;
DE Flags: Precursor;
GN Name=CST6;
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].
RX PubMed=8995380; DOI=10.1074/jbc.272.2.903;
RA Sotiropoulou G., Anisowicz A., Sager R.;
RT "Identification, cloning, and characterization of cystatin M, a novel
RT cysteine proteinase inhibitor, down-regulated in breast cancer.";
RL J. Biol. Chem. 272:903-910(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9099741; DOI=10.1074/jbc.272.16.10853;
RA Ni J., Abrahamson M., Zhang M., Fernandez M.A., Grubb A., Su J., Yu G.L.,
RA Li Y., Parmelee D., Xing L., Coleman T.A., Gentz S., Thotakura R.,
RA Nguyen N., Hesselberg M., Gentz R.;
RT "Cystatin E is a novel human cysteine proteinase inhibitor with structural
RT resemblance to family 2 cystatins.";
RL J. Biol. Chem. 272:10853-10858(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Blood;
RX PubMed=12839564; DOI=10.1046/j.1523-1747.2003.12312.x;
RA Zeeuwen P.L., Dale B.A., de Jongh G.J., van Vlijmen-Willems I.M.,
RA Fleckman P., Kimball J.R., Stephens K., Schalkwijk J.;
RT "The human cystatin M/E gene (CST6): exclusion candidate gene for harlequin
RT ichthyosis.";
RL J. Invest. Dermatol. 121:65-68(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Prostate;
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 [5]
RP CHARACTERIZATION, AND TISSUE SPECIFICITY.
RX PubMed=11348457; DOI=10.1046/j.1523-1747.2001.01309.x;
RA Zeeuwen P.L., Van Vlijmen-Willems I.M., Jansen B.J., Sotiropoulou G.,
RA Curfs J.H., Meis J.F., Janssen J.J., Van Ruissen F., Schalkwijk J.;
RT "Cystatin M/E expression is restricted to differentiated epidermal
RT keratinocytes and sweat glands: a new skin-specific proteinase inhibitor
RT that is a target for cross-linking by transglutaminase.";
RL J. Invest. Dermatol. 116:693-701(2001).
RN [6]
RP FUNCTION, INVOLVEMENT IN ECTD15, VARIANT ECTD15 121-GLN--MET-149 DEL, AND
RP CHARACTERIZATION OF VARIANT ECTD15 121-GLN--MET-149 DEL.
RX PubMed=30425301; DOI=10.1038/s41436-018-0355-3;
RA van den Bogaard E.H.J., van Geel M., van Vlijmen-Willems I.M.J.J.,
RA Jansen P.A.M., Peppelman M., van Erp P.E.J., Atalay S., Venselaar H.,
RA Simon M.E.H., Joosten M., Schalkwijk J., Zeeuwen P.L.J.M.;
RT "Deficiency of the human cysteine protease inhibitor cystatin M/E causes
RT hypotrichosis and dry skin.";
RL Genet. Med. 21:1559-1567(2019).
CC -!- FUNCTION: High affinity inhibitor for cathepsin L, cathepsin L2
CC (cathepsin V), and legumain (PubMed:30425301). Involved in the
CC regulation of epidermal cornification, and hair follicle morphogenesis
CC and maintenance (PubMed:30425301). {ECO:0000269|PubMed:30425301}.
CC -!- INTERACTION:
CC Q15828; O95070: YIF1A; NbExp=3; IntAct=EBI-7163527, EBI-2799703;
CC PRO_0000006648; PRO_0000026502 [Q99538]: LGMN; NbExp=5; IntAct=EBI-29014783, EBI-29020361;
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Restricted to the stratum granulosum of normal
CC skin, the stratum granulosum/spinosum of psoriatic skin, and the
CC secretory coils of eccrine sweat glands. Low expression levels are
CC found in the nasal cavity. {ECO:0000269|PubMed:11348457}.
CC -!- PTM: Substrate for transglutaminases. Acts as an acyl acceptor but not
CC as an acyl donor.
CC -!- DISEASE: Ectodermal dysplasia 15, hypohidrotic/hair type (ECTD15)
CC [MIM:618535]: A form of ectodermal dysplasia, a disorder due to
CC abnormal development of two or more ectodermal structures. ECTD15 is an
CC autosomal recessive form characterized by hypotrichosis and absence of
CC sweating except with extreme exercise. Skin is dry from birth and
CC eczematous lesions may develop in adulthood. Other features include
CC blepharitis and photophobia. {ECO:0000269|PubMed:30425301}. Note=The
CC disease may be caused by variants affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the cystatin family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/CST6ID40178ch11q13.html";
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DR EMBL; U62800; AAB06566.1; -; mRNA.
DR EMBL; U81233; AAB61305.1; -; mRNA.
DR EMBL; AY145051; AAN52757.1; -; Genomic_DNA.
DR EMBL; BC031334; AAH31334.1; -; mRNA.
DR CCDS; CCDS8126.1; -.
DR RefSeq; NP_001314.1; NM_001323.3.
DR PDB; 4N6L; X-ray; 1.95 A; A=29-149.
DR PDB; 4N6M; X-ray; 2.90 A; A/B=29-149.
DR PDB; 4N6N; X-ray; 1.87 A; B=29-149.
DR PDB; 4N6O; X-ray; 1.80 A; B=29-149.
DR PDB; 6FK0; X-ray; 2.90 A; A/B=29-149.
DR PDBsum; 4N6L; -.
DR PDBsum; 4N6M; -.
DR PDBsum; 4N6N; -.
DR PDBsum; 4N6O; -.
DR PDBsum; 6FK0; -.
DR AlphaFoldDB; Q15828; -.
DR SMR; Q15828; -.
DR BioGRID; 107856; 139.
DR IntAct; Q15828; 38.
DR MINT; Q15828; -.
DR STRING; 9606.ENSP00000311313; -.
DR MEROPS; I25.006; -.
DR GlyGen; Q15828; 2 sites, 1 O-linked glycan (1 site).
DR iPTMnet; Q15828; -.
DR PhosphoSitePlus; Q15828; -.
DR BioMuta; CST6; -.
DR DMDM; 2494024; -.
DR jPOST; Q15828; -.
DR MassIVE; Q15828; -.
DR MaxQB; Q15828; -.
DR PaxDb; Q15828; -.
DR PeptideAtlas; Q15828; -.
DR PRIDE; Q15828; -.
DR ProteomicsDB; 60779; -.
DR Antibodypedia; 30046; 318 antibodies from 29 providers.
DR DNASU; 1474; -.
DR Ensembl; ENST00000312134.3; ENSP00000311313.2; ENSG00000175315.3.
DR GeneID; 1474; -.
DR KEGG; hsa:1474; -.
DR MANE-Select; ENST00000312134.3; ENSP00000311313.2; NM_001323.4; NP_001314.1.
DR UCSC; uc001ogr.4; human.
DR CTD; 1474; -.
DR DisGeNET; 1474; -.
DR GeneCards; CST6; -.
DR HGNC; HGNC:2478; CST6.
DR HPA; ENSG00000175315; Tissue enriched (skin).
DR MalaCards; CST6; -.
DR MIM; 601891; gene.
DR MIM; 618535; phenotype.
DR neXtProt; NX_Q15828; -.
DR OpenTargets; ENSG00000175315; -.
DR PharmGKB; PA26979; -.
DR VEuPathDB; HostDB:ENSG00000175315; -.
DR eggNOG; ENOG502SC50; Eukaryota.
DR GeneTree; ENSGT00940000161375; -.
DR HOGENOM; CLU_118168_0_1_1; -.
DR InParanoid; Q15828; -.
DR OMA; CRKTRVT; -.
DR OrthoDB; 1565344at2759; -.
DR PhylomeDB; Q15828; -.
DR PathwayCommons; Q15828; -.
DR SignaLink; Q15828; -.
DR BioGRID-ORCS; 1474; 14 hits in 1066 CRISPR screens.
DR GeneWiki; CST6_(gene); -.
DR GenomeRNAi; 1474; -.
DR Pharos; Q15828; Tbio.
DR PRO; PR:Q15828; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; Q15828; protein.
DR Bgee; ENSG00000175315; Expressed in upper arm skin and 121 other tissues.
DR Genevisible; Q15828; HS.
DR GO; GO:0001533; C:cornified envelope; IEA:Ensembl.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0004869; F:cysteine-type endopeptidase inhibitor activity; TAS:ProtInc.
DR GO; GO:0009653; P:anatomical structure morphogenesis; TAS:ProtInc.
DR GO; GO:0008544; P:epidermis development; IEA:Ensembl.
DR CDD; cd00042; CY; 1.
DR InterPro; IPR000010; Cystatin_dom.
DR InterPro; IPR046350; Cystatin_sf.
DR InterPro; IPR018073; Prot_inh_cystat_CS.
DR Pfam; PF00031; Cystatin; 1.
DR SMART; SM00043; CY; 1.
DR SUPFAM; SSF54403; SSF54403; 1.
DR PROSITE; PS00287; CYSTATIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Disease variant; Disulfide bond; Ectodermal dysplasia;
KW Glycoprotein; Protease inhibitor; Reference proteome; Secreted; Signal;
KW Thiol protease inhibitor.
FT SIGNAL 1..28
FT /evidence="ECO:0000305"
FT CHAIN 29..149
FT /note="Cystatin-M"
FT /id="PRO_0000006648"
FT MOTIF 80..84
FT /note="Secondary area of contact"
FT SITE 36
FT /note="Reactive site"
FT CARBOHYD 137
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 98..113
FT /evidence="ECO:0000250"
FT DISULFID 126..146
FT /evidence="ECO:0000250"
FT VARIANT 121..149
FT /note="Missing (in ECTD15; loss of cystein protease
FT inhibitory activity toward cathepsin L, cathepsin V and
FT legumain)"
FT /evidence="ECO:0000269|PubMed:30425301"
FT /id="VAR_083237"
FT STRAND 38..41
FT /evidence="ECO:0007829|PDB:4N6O"
FT HELIX 46..62
FT /evidence="ECO:0007829|PDB:4N6O"
FT STRAND 65..99
FT /evidence="ECO:0007829|PDB:4N6O"
FT TURN 102..106
FT /evidence="ECO:0007829|PDB:4N6O"
FT HELIX 110..112
FT /evidence="ECO:0007829|PDB:4N6O"
FT HELIX 118..120
FT /evidence="ECO:0007829|PDB:4N6L"
FT STRAND 123..133
FT /evidence="ECO:0007829|PDB:4N6O"
FT HELIX 134..136
FT /evidence="ECO:0007829|PDB:4N6O"
FT STRAND 138..148
FT /evidence="ECO:0007829|PDB:4N6O"
SQ SEQUENCE 149 AA; 16511 MW; 2076A78BFC9FAC8C CRC64;
MARSNLPLAL GLALVAFCLL ALPRDARARP QERMVGELRD LSPDDPQVQK AAQAAVASYN
MGSNSIYYFR DTHIIKAQSQ LVAGIKYFLT MEMGSTDCRK TRVTGDHVDL TTCPLAAGAQ
QEKLRCDFEV LVVPWQNSSQ LLKHNCVQM
