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P01034 (CYTC_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified January 25, 2012. Version 145. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
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Names and origin

Protein namesRecommended name:
Cystatin-C
Alternative name(s):
Cystatin-3
Gamma-trace
Neuroendocrine basic polypeptide
Post-gamma-globulin
Gene names
Name:CST3
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length146 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

As an inhibitor of cysteine proteinases, this protein is thought to serve an important physiological role as a local regulator of this enzyme activity.

Subunit structure

Homodimer.

Subcellular location

Secreted Ref.19.

Tissue specificity

Expressed in submandibular and sublingual saliva but not in parotid saliva (at protein level). Expressed in various body fluids, such as the cerebrospinal fluid and plasma. Expressed in highest levels in the epididymis, vas deferens, brain, thymus, and ovary and the lowest in the submandibular gland. Ref.16 Ref.19

Post-translational modification

The Thr-25 variant is O-glycosylated with a core 1 or possibly core 8 glycan. The signal peptide of the O-glycosylated Thr-25 variant is cleaved between Ala-20 and Val-21. Ref.18

Involvement in disease

Defects in CST3 are the cause of amyloidosis type 6 (AMYL6) [MIM:105150]; also known as hereditary cerebral hemorrhage with amyloidosis (HCHWA), cerebral amyloid angiopathy (CAA) or cerebroarterial amyloidosis Icelandic type. AMYL6 is a hereditary generalized amyloidosis due to cystatin C amyloid deposition. Cystatin C amyloid accumulates in the walls of arteries, arterioles, and sometimes capillaries and veins of the brain, and in various organs including lymphoid tissue, spleen, salivary glands, and seminal vesicles. Amyloid deposition in the cerebral vessels results in cerebral amyloid angiopathy, cerebral hemorrhage and premature stroke. Cystatin C levels in the cerebrospinal fluid are abnormally low. Ref.3 Ref.22

Genetic variations in CST3 are associated with age-related macular degeneration type 11 (ARMD11) [MIM:611953]. ARMD is a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane. Ref.23

Miscellaneous

Potential cerebrospinal fluid marker for the diagnosis of Creutzfeldt-Jakob disease.

Sequence similarities

Belongs to the cystatin family.

Mass spectrometry

Molecular mass is 13334.5829±0.0140 Da from positions 27 - 146. Determined by ESI. Ref.19

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2626 Ref.11 Ref.12 Ref.13 Ref.14
Chain27 – 146120Cystatin-C Ref.1 Ref.3
PRO_0000006639

Regions

Motif81 – 855Secondary area of contact

Sites

Site371Reactive site

Amino acid modifications

Disulfide bond99 ↔ 109 Ref.15 Ref.19
Disulfide bond123 ↔ 143 Ref.15 Ref.19

Natural variations

Natural variant251A → T Associated with ARMD11 and O-glycosylated in region between AA 22-28. Ref.2 Ref.18 Ref.23
Corresponds to variant rs1064039 [ dbSNP | Ensembl ].
VAR_011893
Natural variant941L → Q in AMYL6. Ref.3 Ref.22
Corresponds to variant rs28939068 [ dbSNP | Ensembl ].
VAR_002207

Experimental info

Mutagenesis251A → S: Shows a dual distribution to the Golgi apparatus and to the mitochondria. Ref.17

Secondary structure

.............. 146
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P01034 [UniParc].

Last modified August 1, 1988. Version 1.
Checksum: 75EF049CAE2E8B2B

FASTA14615,799
        10         20         30         40         50         60 
MAGPLRAPLL LLAILAVALA VSPAAGSSPG KPPRLVGGPM DASVEEEGVR RALDFAVGEY 

        70         80         90        100        110        120 
NKASNDMYHS RALQVVRARK QIVAGVNYFL DVELGRTTCT KTQPNLDNCP FHDQPHLKRK 

       130        140 
AFCSFQIYAV PWQGTMTLSK STCQDA 

« Hide

References

« Hide 'large scale' references
[1]"Molecular cloning and sequence analysis of cDNA coding for the precursor of the human cysteine proteinase inhibitor cystatin C."
Abrahamson M., Grubb A., Olafsson I., Lundwall A.
FEBS Lett. 216:229-233(1987) [PubMed: 3495457] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Placenta.
[2]"The human cystatin C gene (CST3) is a member of the cystatin gene family which is localized on chromosome 20."
Saitoh E., Sabatini L.M., Eddy R.L., Shows T.B., Azen E.A., Isemura S., Sanada K.
Biochem. Biophys. Res. Commun. 162:1324-1331(1989) [PubMed: 2764935] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT THR-25.
[3]"Stroke in Icelandic patients with hereditary amyloid angiopathy is related to a mutation in the cystatin C gene, an inhibitor of cysteine proteases."
Levy E., Lopez-Otin C., Ghiso J., Geltner D., Frangione B.
J. Exp. Med. 169:1771-1778(1989) [PubMed: 2541223] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT AMYL6 GLN-94.
Tissue: Brain.
[4]"Structure and expression of the human cystatin C gene."
Abrahamson M., Olafsson I., Palsdottir A., Ulvsbaeck M., Lundwall A., Jensson O., Grubb A.
Biochem. J. 268:287-294(1990) [PubMed: 2363674] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
Tissue: Leukocyte.
[5]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Synovial cell.
[6]"Cloning of human full-length CDSs in BD Creator(TM) system donor vector."
Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A.
Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[7]"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)."
Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S., Neubert P., Kstrang K., Schatten R., Shen B., Henze S., Mar W., Korn B., Zuo D., Hu Y., LaBaer J.
Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[8]"The DNA sequence and comparative analysis of human chromosome 20."
Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., Bird C.P., Blakey S.E. expand/collapse author list , Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.
Nature 414:865-871(2001) [PubMed: 11780052] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[9]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[10]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Brain.
[11]"Human gamma-trace, a basic microprotein: amino acid sequence and presence in the adenohypophysis."
Grubb A., Loefberg H.
Proc. Natl. Acad. Sci. U.S.A. 79:3024-3027(1982) [PubMed: 6283552] [Abstract]
Cited for: PROTEIN SEQUENCE OF 27-146.
[12]"Human cystatin, a new protein inhibitor of cysteine proteinases."
Brzin J., Popovic T., Turk V.
Biochem. Biophys. Res. Commun. 118:103-109(1984) [PubMed: 6365094] [Abstract]
Cited for: PROTEIN SEQUENCE OF 27-76.
[13]"Protein inhibitors of cysteine proteinases. III. Amino-acid sequence of cystatin from chicken egg white."
Turk V., Brzin J., Longer M., Ritonja A., Eropkin M., Borchart U., Machleidt W.
Hoppe-Seyler's Z. Physiol. Chem. 364:1487-1496(1983) [PubMed: 6662498] [Abstract]
Cited for: PROTEIN SEQUENCE OF 27-73.
[14]"Signal peptide prediction based on analysis of experimentally verified cleavage sites."
Zhang Z., Henzel W.J.
Protein Sci. 13:2819-2824(2004) [PubMed: 15340161] [Abstract]
Cited for: PROTEIN SEQUENCE OF 27-41.
[15]"The disulphide bridges of human cystatin C (gamma-trace) and chicken cystatin."
Grubb A., Loefberg H., Barrett A.J.
FEBS Lett. 170:370-374(1984)
Cited for: DISULFIDE BONDS.
[16]"Cystatin C as a potential cerebrospinal fluid marker for the diagnosis of Creutzfeldt-Jakob disease."
Sanchez J.C., Guillaume E., Lescuyer P., Allard L., Carrette O., Scherl A., Burgess J., Corthals G.L., Burkhard P.R., Hochstrasser D.F.
Proteomics 4:2229-2233(2004) [PubMed: 15274116] [Abstract]
Cited for: TISSUE SPECIFICITY.
[17]"A dual Golgi- and mitochondria-localised Ala25Ser precursor cystatin C: an additional tool for characterising intracellular mis-localisation leading to increased AMD susceptibility."
Ratnayaka A., Paraoan L., Spiller D.G., Hiscott P., Nelson G., White M.R., Grierson I.
Exp. Eye Res. 84:1135-1139(2007) [PubMed: 16635487] [Abstract]
Cited for: MUTAGENESIS OF ALA-25.
[18]"Enrichment of glycopeptides for glycan structure and attachment site identification."
Nilsson J., Rueetschi U., Halim A., Hesse C., Carlsohn E., Brinkmalm G., Larson G.
Nat. Methods 6:809-811(2009) [PubMed: 19838169] [Abstract]
Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS], STRUCTURE OF CARBOHYDRATES, MASS SPECTROMETRY, CHARACTERIZATION OF VARIANT THR-25.
Tissue: Cerebrospinal fluid.
[19]"Confident assignment of intact mass tags to human salivary cystatins using top-down Fourier-transform ion cyclotron resonance mass spectrometry."
Ryan C.M., Souda P., Halgand F., Wong D.T., Loo J.A., Faull K.F., Whitelegge J.P.
J. Am. Soc. Mass Spectrom. 21:908-917(2010) [PubMed: 20189825] [Abstract]
Cited for: DISULFIDE BONDS, TISSUE SPECIFICITY, SUBCELLULAR LOCATION, MASS SPECTROMETRY.
Tissue: Saliva.
[20]"Human cystatin C, an amyloidogenic protein, dimerizes through three-dimensional domain swapping."
Janowski R., Kozak M., Jankowska E., Grzonka Z., Grubb A., Abrahamson M., Jaskolski M.
Nat. Struct. Biol. 8:316-320(2001) [PubMed: 11276250] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 27-146.
[21]"3D domain-swapped human cystatin C with amyloid-like intermolecular beta-sheets."
Janowski R., Kozak M., Abrahamson M., Grubb A., Jaskolski M.
Proteins 61:570-578(2005) [PubMed: 16170782] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (3.03 ANGSTROMS) OF 27-146.
[22]"Hereditary cystatin C amyloid angiopathy: identification of the disease-causing mutation and specific diagnosis by polymerase chain reaction based analysis."
Abrahamson M., Jonsdottir S., Olafsson I., Jensson O., Grubb A.
Hum. Genet. 89:377-380(1992) [PubMed: 1352269] [Abstract]
Cited for: VARIANT AMYL6 GLN-94.
[23]"CST3 genotype associated with exudative age related macular degeneration."
Zurdel J., Finckh U., Menzer G., Nitsch R.M., Richard G.
Br. J. Ophthalmol. 86:214-219(2002) [PubMed: 11815350] [Abstract]
Cited for: ASSOCIATION OF VARIANT THR-25 WITH ARMD11.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
X05607 mRNA. Translation: CAA29096.1.
M27891, M27889, M27890 Genomic DNA. Translation: AAA52164.1.
X61681, X61682, X61683 Genomic DNA. Translation: CAA43856.2.
X52255 Genomic DNA. Translation: CAA36497.1.
AK312213 mRNA. Translation: BAG35146.1.
BT006839 mRNA. Translation: AAP35485.1.
CR541988 mRNA. Translation: CAG46785.1.
CR542018 mRNA. Translation: CAG46815.1.
AL121894 Genomic DNA. Translation: CAC05424.1.
CH471133 Genomic DNA. Translation: EAX10137.1.
CH471133 Genomic DNA. Translation: EAX10138.1.
BC013083 mRNA. Translation: AAH13083.1.
BC110305 mRNA. Translation: AAI10306.1.
IPIIPI00032293.
PIRUDHU. S10216.
RefSeqNP_000090.1. NM_000099.2.
UniGeneHs.304682.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1G96X-ray2.50A27-146[»]
1R4CX-ray2.18A/B/C/D/E/F/G/H37-146[»]
1TIJX-ray3.03A/B27-146[»]
3GAXX-ray1.70A/B27-146[»]
3NX0X-ray2.04A/B27-146[»]
ProteinModelPortalP01034.
SMRP01034. Positions 36-146.
ModBaseSearch...

Protein-protein interaction databases

IntActP01034. 4 interactions.
MINTMINT-2857857.
STRINGP01034.

Protein family/group databases

MEROPSI25.004.

Polymorphism databases

DMDM118183.

2D gel databases

DOSAC-COBS-2DPAGEP01034.
UCD-2DPAGEP01034.

Proteomic databases

PeptideAtlasP01034.
PRIDEP01034.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000376925; ENSP00000366124; ENSG00000101439.
ENST00000398409; ENSP00000381446; ENSG00000101439.
ENST00000398411; ENSP00000381448; ENSG00000101439.
GeneID1471.
KEGGhsa:1471.
UCSCuc002wtm.2. human.

Organism-specific databases

CTD1471.
GeneCardsGC20M023608.
H-InvDBHIX0015694.
HGNCHGNC:2475. CST3.
HPACAB000118.
HPA013143.
MIM105150. phenotype.
604312. gene.
611953. phenotype.
neXtProtNX_P01034.
Orphanet85458. Hereditary cerebral hemorrhage with amyloidosis.
PharmGKBPA26976.
GenAtlasSearch...

Phylogenomic databases

eggNOGprNOG20133.
GeneTreeENSGT00570000079039.
HOGENOMHBG717109.
HOVERGENHBG009556.
InParanoidP01034.
OMAASNDAYH.
OrthoDBEOG49GKJ0.
PhylomeDBP01034.

Enzyme and pathway databases

ReactomeREACT_75925. Amyloids.

Gene expression databases

ArrayExpressP01034.
BgeeP01034.
CleanExHS_CST3.
GenevestigatorP01034.
GermOnlineENSG00000101439. Homo sapiens.

Family and domain databases

InterProIPR000010. Prot_inh_cystat.
IPR018073. Prot_inh_cystat_CS.
[Graphical view]
KOK13899.
PfamPF00031. Cystatin. 1 hit.
[Graphical view]
SMARTSM00043. CY. 1 hit.
[Graphical view]
PROSITEPS00287. CYSTATIN. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio6039.
PMAP-CutDBP01034.
SOURCESearch...

Entry information

Entry nameCYTC_HUMAN
AccessionPrimary (citable) accession number: P01034
Secondary accession number(s): B2R5J9, D3DW42, Q6FGW9
Entry history
Integrated into UniProtKB/Swiss-Prot: July 21, 1986
Last sequence update: August 1, 1988
Last modified: January 25, 2012
This is version 145 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Relevant documents

Human chromosome 20

Human chromosome 20: entries, gene names and cross-references to MIM

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

SIMILARITY comments

Index of protein domains and families