Cystatin-A is a protein that in humans is encoded by the CSTAgene.[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:
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.
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]
1 2 3 4 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. PMID12836678.
↑ 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. PMID12423365.
1 2 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. PMID10353845.
↑ 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. PMID14503883.
1 2 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. PMID9585570.
↑ 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. PMID12921779.
↑ 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. PMID20116931.
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. PMID3122506.
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. PMID9769367.
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. PMID107702.
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. PMID107703.
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. PMID1286667. S2CID41855774.
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. PMID2004763.
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. PMID2424340.
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. PMID2768224.
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. PMID3067731.
Davies ME, Barrett AJ (1984). "Immunolocalization of human cystatins in neutrophils and lymphocytes". Histochemistry. 80 (4): 373–377. doi:10.1007/BF00495420. PMID6429090. S2CID13559202.
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. PMID6689312.
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. PMID7541394. S2CID25265556.
Tate S, Ushioda T, Utsunomiya-Tate N, Shibuya K, Ohyama Y, Nakano Y, etal. (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. PMID7578072.{{cite journal}}: CS1 maint: overridden setting (link)
Martin JR, Craven CJ, Jerala R, Kroon-Zitko L, Zerovnik E, Turk V, etal. (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. PMID7869384.
1cyu: SOLUTION NMR STRUCTURE OF RECOMBINANT HUMAN CYSTATIN A UNDER THE CONDITION OF PH 3.8 AND 310K
1cyv: SOLUTION NMR STRUCTURE OF RECOMBINANT HUMAN CYSTATIN A UNDER THE CONDITION OF PH 3.8 AND 310K
1dvc: SOLUTION NMR STRUCTURE OF HUMAN STEFIN A AT PH 5.5 AND 308K, NMR, MINIMIZED AVERAGE STRUCTURE
1dvd: SOLUTION NMR STRUCTURE OF HUMAN STEFIN A AT PH 5.5 AND 308K, NMR, 17 STRUCTURES
1gd3: refined solution structure of human cystatin A
1gd4: SOLUTION STRUCTURE OF P25S CYSTATIN A
1n9j: Solution Structure of the 3D domain swapped dimer of Stefin A
1nb3: Crystal structure of stefin A in complex with cathepsin H: N-terminal residues of inhibitors can adapt to the active sites of endo-and exopeptidases
1nb5: Crystal structure of stefin A in complex with cathepsin H
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