{{Short description|Protein-coding gene in the species Homo sapiens}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox_gene}} '''Cystatin-A''' is a protein that in humans is encoded by the ''CSTA'' gene.<ref name="Hsieh_1991">{{cite journal | vauthors = Hsieh WT, Barrick JL, Berrettini WH, Chan MM, Fong D | title = A PstI DNA polymorphism in the human stefin A gene (STF 1) | journal = Nucleic Acids Research | volume = 19 | issue = 7 | pages = 1722 | date = April 1991 | pmid = 1674139 | pmc = 333958 | doi = 10.1093/nar/19.7.1722-a }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: CSTA cystatin A (stefin A) | url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=1475 }}</ref>
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.<ref name="entrez" />
== 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.<ref name="Kariya_2000">{{cite journal | vauthors = Shimba N, Kariya E, Tate S, Kaji H, Kainosho M | title = Structural comparison between wild-type and P25S human cystatin A by NMR spectroscopy. Does this mutation affect the alpha-helix conformation? | journal = Journal of Structural and Functional Genomics | volume = 1 | issue = 1 | pages = 26–42 | date = 2000 | pmid = 12836678 | doi = 10.1023/A:1011380315619 }}</ref> The protein has three main functional regions:
* An N-terminal region with a conserved glycine<ref name="Kariya_2000" /> * Two β-hairpin loops (the first loop contains the important QVVAG sequence shown in blue in the image)<ref name="Kariya_2000" /> * A C-terminal region that helps stabilize the structure<ref name="Kariya_2000" />
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<ref>{{cite journal | vauthors = Pavlova A, Björk I | title = 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 | journal = European Journal of Biochemistry | volume = 269 | issue = 22 | pages = 5649–5658 | date = November 2002 | pmid = 12423365 | doi = 10.1046/j.1432-1033.2002.03273.x }}</ref> * The N-terminal domain contributes about 40% of the overall binding energy<ref name="Pavlova_1999">{{cite journal | vauthors = Estrada S, Pavlova A, Björk I | title = 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 | journal = Biochemistry | volume = 38 | issue = 22 | pages = 7339–7345 | date = June 1999 | pmid = 10353845 | doi = 10.1021/bi990003s }}</ref> * Pro-3 and Ile-2 are particularly important for energy binding<ref name="Pavlova_1999" />
== 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.<ref>{{cite journal | vauthors = Hsieh WT, Barrick JL, Berrettini WH, Chan MM, Fong D | title = A PstI DNA polymorphism in the human stefin A gene (STF 1) | journal = Nucleic Acids Research | volume = 19 | issue = 7 | pages = 1722 | date = April 1991 | pmid = 1674139 | pmc = 333958 | doi = 10.1093/nar/19.7.1722-a }}</ref>
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<ref name="Bjork_Ingemar_2003">{{cite journal | vauthors = Pavlova A, Björk I | title = 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 | journal = Biochemistry | volume = 42 | issue = 38 | pages = 11326–11333 | date = September 2003 | pmid = 14503883 | doi = 10.1021/bi030119v }}</ref><ref name="Nycander_1998">{{cite journal | vauthors = Estrada S, Nycander M, Hill NJ, Craven CJ, Waltho JP, Björk I | title = 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 | journal = Biochemistry | volume = 37 | issue = 20 | pages = 7551–7560 | date = May 1998 | pmid = 9585570 | doi = 10.1021/bi980026r }}</ref> and CTSL1.<ref name="Nycander_1998" /><ref name=pmid12921779>{{cite journal | vauthors = Majerle A, Jerala R | title = Protein inhibitors form complexes with procathepsin L and augment cleavage of the propeptide | journal = Archives of Biochemistry and Biophysics | volume = 417 | issue = 1 | pages = 53–58 | date = September 2003 | pmid = 12921779 | doi = 10.1016/S0003-9861(03)00319-9 }}</ref>
== Clinical significance == Altered levels of cystatin A have been observed in several disease states, particularly in skin disorders and certain cancers.<ref>{{cite journal | vauthors = Rinne A | title = Epidermal SH-protease inhibitor (ACPI, cystatin A) in cancer. A short historical review | journal = Pathology, Research and Practice | volume = 206 | issue = 4 | pages = 259–262 | date = April 2010 | pmid = 20116931 | doi = 10.1016/j.prp.2009.12.005 }}</ref> Its role as a protease inhibitor makes it potentially valuable as both a diagnostic marker and therapeutic target.<ref>{{cite journal | vauthors = Xie Q, Liu L, Chen X, Cheng Y, Li J, Zhang X, Xu N, Han Y, Liu H, Wei L, Peng J, Shen A | display-authors = 6 | title = Identification of Cysteine Protease Inhibitor CST2 as a Potential Biomarker for Colorectal Cancer | journal = Journal of Cancer | volume = 12 | issue = 17 | pages = 5144–5152 | date = 2021-06-22 | pmid = 34335931 | doi = 10.7150/jca.53983 | pmc = 8317524 }}</ref>
== See also == * Peptide Transporter Carbon Starvation (cstA) Family
== References == {{reflist}}
== Further reading == {{refbegin | 2}} * {{cite journal | vauthors = Järvinen M, Rinne A, Hopsu-Havu VK | title = Human cystatins in normal and diseased tissues--a review | journal = Acta Histochemica | volume = 82 | issue = 1 | pages = 5–18 | year = 1988 | pmid = 3122506 | doi = 10.1016/s0065-1281(87)80043-0 }} * {{cite journal | vauthors = Brown WM, Dziegielewska KM | title = Friends and relations of the cystatin superfamily--new members and their evolution | journal = Protein Science | volume = 6 | issue = 1 | pages = 5–12 | date = January 1997 | pmid = 9007972 | pmc = 2143511 | doi = 10.1002/pro.5560060102 }} * {{cite journal | vauthors = Kos J, Lah TT | title = Cysteine proteinases and their endogenous inhibitors: target proteins for prognosis, diagnosis and therapy in cancer (review) | journal = Oncology Reports | volume = 5 | issue = 6 | pages = 1349–1361 | year = 1998 | pmid = 9769367 | doi = 10.3892/or.5.6.1349 }} * {{cite journal | vauthors = Rinne A, Järvinen M, Räsänen O | title = A protein reminiscent of the epidermal SH-protease inhibitor occurs in squamous epithelia of man and rat | journal = Acta Histochemica | volume = 63 | issue = 2 | pages = 183–192 | year = 1979 | pmid = 107702 | doi = 10.1016/s0065-1281(78)80024-5 }} * {{cite journal | vauthors = Räsänen O, Järvinen M, Rinne A | title = Localization of the human SH-protease inhibitor in the epidermis. Immunofluorescent studies | journal = Acta Histochemica | volume = 63 | issue = 2 | pages = 193–196 | year = 1979 | pmid = 107703 | doi = 10.1016/s0065-1281(78)80025-7 }} * {{cite journal | vauthors = Rasmussen HH, van Damme J, Puype M, Gesser B, Celis JE, Vandekerckhove J | title = Microsequences of 145 proteins recorded in the two-dimensional gel protein database of normal human epidermal keratinocytes | journal = Electrophoresis | volume = 13 | issue = 12 | pages = 960–969 | date = December 1992 | pmid = 1286667 | doi = 10.1002/elps.11501301199 | s2cid = 41855774 }} * {{cite journal | vauthors = Madsen P, Rasmussen HH, Leffers H, Honoré B, Dejgaard K, Olsen E, Kiil J, Walbum E, Andersen AH, Basse B | display-authors = 6 | title = Molecular cloning, occurrence, and expression of a novel partially secreted protein "psoriasin" that is highly up-regulated in psoriatic skin | journal = The Journal of Investigative Dermatology | volume = 97 | issue = 4 | pages = 701–712 | date = October 1991 | pmid = 1940442 | doi = 10.1111/1523-1747.ep12484041 | doi-access = free }} * {{cite journal | vauthors = Hsieh WT, Fong D, Sloane BF, Golembieski W, Smith DI | title = Mapping of the gene for human cysteine proteinase inhibitor stefin A, STF1, to chromosome 3cen-q21 | journal = Genomics | volume = 9 | issue = 1 | pages = 207–209 | date = January 1991 | pmid = 2004763 | doi = 10.1016/0888-7543(91)90241-6 }} * {{cite journal | vauthors = Rinne A, Järvinen M, Dorn A, Alavaikko M, Jokinen K, Hopsu-Havu VK | title = [Low-molecular cysteine protease inhibitors in the human palatal tonsil] | journal = Anatomischer Anzeiger | volume = 161 | issue = 3 | pages = 215–230 | year = 1986 | pmid = 2424340 }} * {{cite journal | vauthors = Kartasova T, Cornelissen BJ, Belt P, van de Putte P | title = Effects of UV, 4-NQO and TPA on gene expression in cultured human epidermal keratinocytes | journal = Nucleic Acids Research | volume = 15 | issue = 15 | pages = 5945–5962 | date = August 1987 | pmid = 2442723 | pmc = 306060 | doi = 10.1093/nar/15.15.5945 }} * {{cite journal | vauthors = Takeda A, Kaji H, Nakaya K, Nakamura Y, Samejima T | title = Comparative studies on the primary structure of human cystatin as from epidermis, liver, spleen, and leukocytes | journal = Journal of Biochemistry | volume = 105 | issue = 6 | pages = 986–991 | date = June 1989 | pmid = 2768224 | doi = 10.1093/oxfordjournals.jbchem.a122792 }} * {{cite journal | vauthors = Strauss M, Stollwerk J, Lenarcic B, Turk V, Jany KD, Gassen HG | title = Chemical synthesis of a gene for human stefin A and its expression in E. coli | journal = Biological Chemistry Hoppe-Seyler | volume = 369 | issue = 9 | pages = 1019–1030 | date = September 1988 | pmid = 3067731 | doi = 10.1515/bchm3.1988.369.2.1019 }} * {{cite journal | vauthors = Davies ME, Barrett AJ | title = Immunolocalization of human cystatins in neutrophils and lymphocytes | journal = Histochemistry | volume = 80 | issue = 4 | pages = 373–377 | year = 1984 | pmid = 6429090 | doi = 10.1007/BF00495420 | s2cid = 13559202 }} * {{cite journal | vauthors = Machleidt W, Borchart U, Fritz H, Brzin J, Ritonja A, Turk V | title = Protein inhibitors of cysteine proteinases. II. Primary structure of stefin, a cytosolic protein inhibitor of cysteine proteinases from human polymorphonuclear granulocytes | journal = Hoppe-Seyler's Zeitschrift für Physiologische Chemie | volume = 364 | issue = 11 | pages = 1481–1486 | date = November 1983 | pmid = 6689312 | doi = 10.1515/bchm2.1983.364.2.1481 }} * {{cite journal | vauthors = Söderström KO, Laato M, Wu P, Hopsu-Havu VK, Nurmi M, Rinne A | title = Expression of acid cysteine proteinase inhibitor (ACPI) in the normal human prostate, benign prostatic hyperplasia and adenocarcinoma | journal = International Journal of Cancer | volume = 62 | issue = 1 | pages = 1–4 | date = July 1995 | pmid = 7541394 | doi = 10.1002/ijc.2910620102 | s2cid = 25265556 }} * {{cite journal | vauthors = Tate S, Ushioda T, Utsunomiya-Tate N, Shibuya K, Ohyama Y, Nakano Y, Kaji H, Inagaki F, Samejima T, Kainosho M | display-authors = 6 | title = 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 | journal = Biochemistry | volume = 34 | issue = 45 | pages = 14637–14648 | date = November 1995 | pmid = 7578072 | doi = 10.1021/bi00045a004 }} * {{cite journal | vauthors = Martin JR, Craven CJ, Jerala R, Kroon-Zitko L, Zerovnik E, Turk V, Waltho JP | title = The three-dimensional solution structure of human stefin A | journal = Journal of Molecular Biology | volume = 246 | issue = 2 | pages = 331–343 | date = February 1995 | pmid = 7869384 | doi = 10.1006/jmbi.1994.0088 }} * {{cite journal | vauthors = Steinert PM, Marekov LN | title = Direct evidence that involucrin is a major early isopeptide cross-linked component of the keratinocyte cornified cell envelope | journal = The Journal of Biological Chemistry | volume = 272 | issue = 3 | pages = 2021–2030 | date = January 1997 | pmid = 8999895 | doi = 10.1074/jbc.272.3.2021 | doi-access = free }} {{refend}}
== External links == * [https://web.archive.org/web/20130928064442/http://www.ebi.ac.uk/pdbe/quips?story=Cystatin Cystatin: a protein that flips out!] QUite Interesting PDB Structure article at [http://www.pdbe.org PDBe] * The MEROPS online database for peptidases and their inhibitors: [http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=I25.001 I25.001] {{PDB Gallery|geneid=1475}}