Reviewed, UniProtKB/Swiss-Prot P01034 (CYTC_HUMAN)

Names and origin

Protein names

Recommended name:
    Cystatin-C
Alternative name(s):
    Cystatin-3
    Neuroendocrine basic polypeptide
    Gamma-trace
    Post-gamma-globulin

Gene names

Name:

CST3

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	146 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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.
Tissue specificity	Found 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
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 hemorrage and premature stroke. Cystatin C levels in the cerebrospinal fluid are abnormally low. Ref.3 Ref.20 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.21
Miscellaneous	Potential cerebrospinal fluid marker for the diagnosis of Creutzfeldt-Jakob disease.
Sequence similarities	Belongs to the cystatin family.

Ontologies

Keywords
Cellular component	Amyloid Secreted
Coding sequence diversity	Polymorphism
Disease	Age-related macular degeneration Amyloidosis Disease mutation
Domain	Signal
Molecular function	Protease inhibitor Thiol protease inhibitor
PTM	Disulfide bond
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	defense response Inferred from direct assay. Source: UniProtKB fibril organization Inferred from genetic interaction. Source: UniProtKB negative regulation of blood vessel remodeling Inferred from expression pattern. Source: UniProtKB negative regulation of collagen catabolic process Inferred from expression pattern. Source: UniProtKB negative regulation of elastin catabolic process Inferred from mutant phenotype. Source: UniProtKB negative regulation of extracellular matrix disassembly Inferred from expression pattern. Source: UniProtKB negative regulation of histolysis Inferred by curator. Source: UniProtKB negative regulation of peptidase activity Inferred from direct assay. Source: UniProtKB
Cellular component	extracellular space Inferred from direct assay. Source: UniProtKB
Molecular function	beta-amyloid binding Inferred from physical interaction. Source: UniProtKB cysteine-type endopeptidase inhibitor activity Inferred from direct assay. Source: UniProtKB protease binding Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 26

26

Ref.11 Ref.12 Ref.13 Ref.14

Chain

27 – 146

120

Cystatin-C Ref.3 Ref.1

PRO_0000006639

Regions

Motif

81 – 85

5

Secondary area of contact

Sites

Site

37

1

Reactive site

Amino acid modifications

Disulfide bond

99 ↔ 109

Ref.15

Disulfide bond

123 ↔ 143

Ref.15

Natural variations

Natural variant

25

1

A → T Associated with ARMD11. dbSNP rs1064039. Ref.21 Ref.2

VAR_011893

Natural variant

94

1

L → Q in AMYL6. Ref.3 Ref.20

VAR_002207

Experimental info

Mutagenesis

25

1

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

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

146

Helix Strand Turn

Details...

Helix

47 – 63

17

Beta strand

67 – 100

34

Helix

106 – 108

3

Turn

115 – 117

3

Beta strand

120 – 130

11

Helix

131 – 133

3

Beta strand

135 – 145

11

Sequences

	Sequence		Length	Mass (Da)
	P01034-1 [UniParc]. Last modified August 1, 1988. Version 1. Checksum: 75EF049CAE2E8B2B	FASTA	146	15,799
	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

References

	« Hide 'large scale' referencesShow '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. , 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. , 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. , 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]	"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.
[19]	"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.
[20]	"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.
[21]	"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

EMBLGenBankDDBJ

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.
BC013083 mRNA. Translation: AAH13083.1.
BC110305 mRNA. Translation: AAI10306.1.

IPI

IPI00032293.

PIR

UDHU. S10216.

RefSeq

NP_000090.1.

UniGene

Hs.304682

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1G96	X-ray	2.50	A	27-146	[»]
1R4C	X-ray	2.18	A/B/C/D/E/F/G/H	37-146	[»]
1TIJ	X-ray	3.03	A/B	27-146	[»]

ModBase

Search...

Protein-protein interaction databases

IntAct

P01034. 2 interactions.

Protein family/group databases

MEROPS

I25.004.

2-D gel databases

DOSAC-COBS-2DPAGE

P01034.

Proteomic databases

PeptideAtlas

P01034.

PRIDE

P01034.

Genome annotation databases

Ensembl

ENSG00000101439. Homo sapiens. [Contig view]

GeneID

1471.

KEGG

hsa:1471.

Organism-specific databases

GeneCards

GC20M023562.

HGNC

HGNC:2475. CST3.

HPA

CAB000118.
HPA013143.

MIM

105150. phenotype.
604312. gene.
611953. phenotype.

Orphanet

69. Amyloidosis.
85458. Cerebral hemorrhage with amyloidosis, hereditary.

PharmGKB

PA26976.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P01034.

HOVERGEN

P01034.

OMA

P01034. FQIYTVP.

Gene expression databases

ArrayExpress

P01034.

Bgee

P01034.

CleanEx

HS_CST3.

GermOnline

ENSG00000101439. Homo sapiens.

Family and domain databases

InterPro

IPR000010. Prot_inh_cystat.
IPR018073. Prot_inh_cystat_CS.
[Graphical view]

Pfam

PF00031. Cystatin. 1 hit.
[Graphical view]

ProDom

PD001231. Prot_inh_I25A_B. 1 hit.
[Graphical view] [Entries sharing at least one domain]

SMART

SM00043. CY. 1 hit.
[Graphical view]

PROSITE

PS00287. CYSTATIN. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

6039.

PMAP-CutDB

P01034.

SOURCE

Search...

Entry information

Entry name

CYTC_HUMAN

Accession

Primary (citable) accession number: P01034
Secondary accession number(s): B2R5J9, Q6FGW9

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 21, 1986
Last sequence update:	August 1, 1988
Last modified:	June 16, 2009
This is version 118 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)