Cystatin A

CSTA
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1CYU, 1CYV, 1DVC, 1DVD, 1GD3, 1GD4, 1N9J, 1NB3, 1NB5, 3K9M, 3KFQ, 3KSE
Identifiers
Aliases	CSTA, AREI, STF1, STFA, Cystatin A, PSS4
External IDs	OMIM: 184600; MGI: 1924020; HomoloGene: 3819; GeneCards: CSTA; OMA:CSTA - orthologs
Gene location (Human) Chr. Chromosome 3 (human)[1] Band 3q21.1 Start 122,325,248 bp[1] End 122,341,969 bp[1]
Gene location (Mouse) Chr. Chromosome 16 (mouse)[2] Band 16|16 B3 Start 36,041,838 bp[2] End 36,077,810 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in mucosa of pharynx oral cavity gums gingival epithelium body of tongue human penis vulva superior surface of tongue epithelium of nasopharynx skin of thigh Top expressed in granulocyte zygote morula blastocyst blood right kidney proximal tubule suprachiasmatic nucleus secondary oocyte primary oocyte More reference expression data BioGPS More reference expression data
Gene ontology Molecular function peptidase inhibitor activity protease binding protein-macromolecule adaptor activity endopeptidase inhibitor activity structural molecule activity cysteine-type endopeptidase inhibitor activity Cellular component cytoplasm intracellular anatomical structure cornified envelope extracellular space nucleus cytosol Biological process negative regulation of proteolysis peptide cross-linking negative regulation of peptidase activity cell adhesion keratinocyte differentiation negative regulation of endopeptidase activity cornification cell-cell adhesion Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1475 76770 Ensembl ENSG00000121552 ENSMUSG00000095620 UniProt P01040 Q9D8D6 RefSeq (mRNA) NM_005213 NM_029733 NM_001384090 RefSeq (protein) NP_005204 NP_084009 NP_001371019 Location (UCSC) Chr 3: 122.33 – 122.34 Mb Chr 16: 36.04 – 36.08 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Cystatin-A is a protein that in humans is encoded by the CSTA gene.^[5][6]

The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (stefins), type 2 cystatins, and kininogens. This gene encodes a stefin that functions as a cysteine protease inhibitor, forming tight complexes with papain and the cathepsins B, H, and L. The protein is one of the precursor proteins of cornified cell envelope in keratinocytes and plays a role in epidermal development and maintenance. Stefins have been proposed as prognostic and diagnostic tools for cancer.^[6]

Structure and Inhibatory Mechanism

The structure of cystatin A features a wedge-like shape that's typical of cysteine protease inhibitors. This shape is critical for how it blocks protease activity.^[7] The protein has three main functional regions:

• An N-terminal region with a conserved glycine^[7]
• Two β-hairpin loops (the first loop contains the important QVVAG sequence shown in blue in the image)^[7]
• A C-terminal region that helps stabilize the structure^[7]

These three regions work together to form the functional core that fits into the catalytic cleft of target proteases. The inhibitory mechanism depends on specific structural features:

• Leu73 in the second binding loop plays a crucial role in the inhibitory activity^[8]
• The N-terminal domain contributes about 40% of the overall binding energy^[9]
• Pro-3 and Ile-2 are particularly important for energy binding^[9]

Function

Cystatin A mainly works as an inhibitor of cysteine proteases, with strong binding to papain and cathepsins B, H, and L. It also serves as a building block for the cornified cell envelope in skin cells and helps with skin growth and maintenance.^[10]

In tissues, cystatin A helps regulate protein breakdown by controlling the activity of these proteases. This regulation is important for normal cell function and can be disrupted in certain diseases.

Interactions

Cystatin A has been shown to interact with Cathepsin B^[11][12] and CTSL1.^[12][13]

Clinical Significance

Altered levels of cystatin A have been observed in several disease states, particularly in skin disorders and certain cancers.^[14] Its role as a protease inhibitor makes it potentially valuable as both a diagnostic marker and therapeutic target.^[15]

See also

• Peptide Transporter Carbon Starvation (cstA) Family

References

1. GRCh38: Ensembl release 89: ENSG00000121552 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000095620 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Hsieh WT, Barrick JL, Berrettini WH, Chan MM, Fong D (April 1991). "A PstI DNA polymorphism in the human stefin A gene (STF 1)". Nucleic Acids Research. 19 (7): 1722. doi:10.1093/nar/19.7.1722-a. PMC 333958. PMID 1674139.
6. "Entrez Gene: CSTA cystatin A (stefin A)".
7. Shimba N, Kariya E, Tate S, Kaji H, Kainosho M (2000). "Structural comparison between wild-type and P25S human cystatin A by NMR spectroscopy. Does this mutation affect the alpha-helix conformation?". Journal of Structural and Functional Genomics. 1 (1): 26–42. doi:10.1023/A:1011380315619. PMID 12836678.
8. Pavlova A, Björk I (November 2002). "The role of the second binding loop of the cysteine protease inhibitor, cystatin A (stefin A), in stabilizing complexes with target proteases is exerted predominantly by Leu73". European Journal of Biochemistry. 269 (22): 5649–5658. doi:10.1046/j.1432-1033.2002.03273.x. PMID 12423365.
9. Estrada S, Pavlova A, Björk I (June 1999). "The contribution of N-terminal region residues of cystatin A (stefin A) to the affinity and kinetics of inhibition of papain, cathepsin B, and cathepsin L". Biochemistry. 38 (22): 7339–7345. doi:10.1021/bi990003s. PMID 10353845.
10. Hsieh WT, Barrick JL, Berrettini WH, Chan MM, Fong D (April 1991). "A PstI DNA polymorphism in the human stefin A gene (STF 1)". Nucleic Acids Research. 19 (7): 1722. doi:10.1093/nar/19.7.1722-a. PMC 333958. PMID 1674139.
11. Pavlova A, Björk I (September 2003). "Grafting of features of cystatins C or B into the N-terminal region or second binding loop of cystatin A (stefin A) substantially enhances inhibition of cysteine proteinases". Biochemistry. 42 (38): 11326–11333. doi:10.1021/bi030119v. PMID 14503883.
12. Estrada S, Nycander M, Hill NJ, Craven CJ, Waltho JP, Björk I (May 1998). "The role of Gly-4 of human cystatin A (stefin A) in the binding of target proteinases. Characterization by kinetic and equilibrium methods of the interactions of cystatin A Gly-4 mutants with papain, cathepsin B, and cathepsin L". Biochemistry. 37 (20): 7551–7560. doi:10.1021/bi980026r. PMID 9585570.
13. Majerle A, Jerala R (September 2003). "Protein inhibitors form complexes with procathepsin L and augment cleavage of the propeptide". Archives of Biochemistry and Biophysics. 417 (1): 53–58. doi:10.1016/S0003-9861(03)00319-9. PMID 12921779.
14. Rinne A (April 2010). "Epidermal SH-protease inhibitor (ACPI, cystatin A) in cancer. A short historical review". Pathology, Research and Practice. 206 (4): 259–262. doi:10.1016/j.prp.2009.12.005. PMID 20116931.
15. Xie Q, Liu L, Chen X, Cheng Y, Li J, Zhang X, et al. (2021-06-22). "Identification of Cysteine Protease Inhibitor CST2 as a Potential Biomarker for Colorectal Cancer". Journal of Cancer. 12 (17): 5144–5152. doi:10.7150/jca.53983. PMC 8317524. PMID 34335931.

Further reading

• Järvinen M, Rinne A, Hopsu-Havu VK (1988). "Human cystatins in normal and diseased tissues--a review". Acta Histochemica. 82 (1): 5–18. doi:10.1016/s0065-1281(87)80043-0. PMID 3122506.
• Brown WM, Dziegielewska KM (January 1997). "Friends and relations of the cystatin superfamily--new members and their evolution". Protein Science. 6 (1): 5–12. doi:10.1002/pro.5560060102. PMC 2143511. PMID 9007972.
• Kos J, Lah TT (1998). "Cysteine proteinases and their endogenous inhibitors: target proteins for prognosis, diagnosis and therapy in cancer (review)". Oncology Reports. 5 (6): 1349–1361. doi:10.3892/or.5.6.1349. PMID 9769367.
• Rinne A, Järvinen M, Räsänen O (1979). "A protein reminiscent of the epidermal SH-protease inhibitor occurs in squamous epithelia of man and rat". Acta Histochemica. 63 (2): 183–192. doi:10.1016/s0065-1281(78)80024-5. PMID 107702.
• Räsänen O, Järvinen M, Rinne A (1979). "Localization of the human SH-protease inhibitor in the epidermis. Immunofluorescent studies". Acta Histochemica. 63 (2): 193–196. doi:10.1016/s0065-1281(78)80025-7. PMID 107703.
• Rasmussen HH, van Damme J, Puype M, Gesser B, Celis JE, Vandekerckhove J (December 1992). "Microsequences of 145 proteins recorded in the two-dimensional gel protein database of normal human epidermal keratinocytes". Electrophoresis. 13 (12): 960–969. doi:10.1002/elps.11501301199. PMID 1286667. S2CID 41855774.
• Madsen P, Rasmussen HH, Leffers H, Honoré B, Dejgaard K, Olsen E, et al. (October 1991). "Molecular cloning, occurrence, and expression of a novel partially secreted protein "psoriasin" that is highly up-regulated in psoriatic skin". The Journal of Investigative Dermatology. 97 (4): 701–712. doi:10.1111/1523-1747.ep12484041. PMID 1940442.
• Hsieh WT, Fong D, Sloane BF, Golembieski W, Smith DI (January 1991). "Mapping of the gene for human cysteine proteinase inhibitor stefin A, STF1, to chromosome 3cen-q21". Genomics. 9 (1): 207–209. doi:10.1016/0888-7543(91)90241-6. PMID 2004763.
• Rinne A, Järvinen M, Dorn A, Alavaikko M, Jokinen K, Hopsu-Havu VK (1986). "[Low-molecular cysteine protease inhibitors in the human palatal tonsil]". Anatomischer Anzeiger. 161 (3): 215–230. PMID 2424340.
• Kartasova T, Cornelissen BJ, Belt P, van de Putte P (August 1987). "Effects of UV, 4-NQO and TPA on gene expression in cultured human epidermal keratinocytes". Nucleic Acids Research. 15 (15): 5945–5962. doi:10.1093/nar/15.15.5945. PMC 306060. PMID 2442723.
• Takeda A, Kaji H, Nakaya K, Nakamura Y, Samejima T (June 1989). "Comparative studies on the primary structure of human cystatin as from epidermis, liver, spleen, and leukocytes". Journal of Biochemistry. 105 (6): 986–991. doi:10.1093/oxfordjournals.jbchem.a122792. PMID 2768224.
• Strauss M, Stollwerk J, Lenarcic B, Turk V, Jany KD, Gassen HG (September 1988). "Chemical synthesis of a gene for human stefin A and its expression in E. coli". Biological Chemistry Hoppe-Seyler. 369 (9): 1019–1030. doi:10.1515/bchm3.1988.369.2.1019. PMID 3067731.
• Davies ME, Barrett AJ (1984). "Immunolocalization of human cystatins in neutrophils and lymphocytes". Histochemistry. 80 (4): 373–377. doi:10.1007/BF00495420. PMID 6429090. S2CID 13559202.
• Machleidt W, Borchart U, Fritz H, Brzin J, Ritonja A, Turk V (November 1983). "Protein inhibitors of cysteine proteinases. II. Primary structure of stefin, a cytosolic protein inhibitor of cysteine proteinases from human polymorphonuclear granulocytes". Hoppe-Seyler's Zeitschrift für Physiologische Chemie. 364 (11): 1481–1486. doi:10.1515/bchm2.1983.364.2.1481. PMID 6689312.
• Söderström KO, Laato M, Wu P, Hopsu-Havu VK, Nurmi M, Rinne A (July 1995). "Expression of acid cysteine proteinase inhibitor (ACPI) in the normal human prostate, benign prostatic hyperplasia and adenocarcinoma". International Journal of Cancer. 62 (1): 1–4. doi:10.1002/ijc.2910620102. PMID 7541394. S2CID 25265556.
• Tate S, Ushioda T, Utsunomiya-Tate N, Shibuya K, Ohyama Y, Nakano Y, et al. (November 1995). "Solution structure of a human cystatin A variant, cystatin A2-98 M65L, by NMR spectroscopy. A possible role of the interactions between the N- and C-termini to maintain the inhibitory active form of cystatin A". Biochemistry. 34 (45): 14637–14648. doi:10.1021/bi00045a004. PMID 7578072.
• Martin JR, Craven CJ, Jerala R, Kroon-Zitko L, Zerovnik E, Turk V, et al. (February 1995). "The three-dimensional solution structure of human stefin A". Journal of Molecular Biology. 246 (2): 331–343. doi:10.1006/jmbi.1994.0088. PMID 7869384.
• Steinert PM, Marekov LN (January 1997). "Direct evidence that involucrin is a major early isopeptide cross-linked component of the keratinocyte cornified cell envelope". The Journal of Biological Chemistry. 272 (3): 2021–2030. doi:10.1074/jbc.272.3.2021. PMID 8999895.

External links

• Cystatin: a protein that flips out! QUite Interesting PDB Structure article at PDBe
• The MEROPS online database for peptidases and their inhibitors: I25.001