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Gene Review

CSTA  -  cystatin A (stefin A)

Homo sapiens

Synonyms: AREI, Cystatin-A, Cystatin-AS, STF1, STFA, ...
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Disease relevance of CSTA


High impact information on CSTA


Chemical compound and disease context of CSTA


Biological context of CSTA

  • 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 [12].
  • The kinetics of binding to papain were consistent with a simple reversible bimolecular reaction mechanism, indicating that cystatin A, like chicken cystatin and cystatin C, binds to papain with no appreciable conformational adaptation of either reacting protein [13].
  • Amino acid sequence determination revealed the presence of stefin A and stefin B type inhibitors and two new inhibitors, designated as porcine stefin D1 and stefin D2 [14].
  • Overexpression of stefin A in human esophageal squamous cell carcinoma cells inhibits tumor cell growth, angiogenesis, invasion, and metastasis [3].
  • We continuously measured cardiac output (Qt) and pulmonary artery, left atrial, airway, and pleural pressures and intermittently measured arterial and mixed venous blood gas tensions and static and dynamic compliance (CSTA, CDYN) with an 18 ml/kg test inflation [15].

Anatomical context of CSTA


Associations of CSTA with chemical compounds

  • Cystatin A, a cysteine proteinase inhibitor, is a cornified cell envelope constituent expressed in the upper epidermis [16].
  • The near-UV spectroscopic changes induced by the binding of recombinant human cystatin A to papain were appreciably different from those induced by cystatin C, reflecting mainly interactions involving the single tryptophan of cystatin C, Trp-106 [13].
  • Cystatin A promoter activity was not affected by cotransfection of vitamin D(3) receptor or retinoid X receptor [2].
  • Similar rates of refolding (6.2s-1 and 7.2 s-1 for ellipticity at 230 and 280 nm, respectively) were observed for stefin A denatured in 66% (vol/vol) TFE, pH 3.3, when refolding to the same final conditions [21].
  • This finding is in agreement with previous conclusions that glycine in this position is essential for tight binding of cystatin A to cysteine proteinases by allowing optimal interaction of the N-terminal region of the inhibitor with the enzyme [22].

Physical interactions of CSTA

  • Cystatin A bound tightly and rapidly to papain and cathepsin L, with dissociation equilibrium constants of approximately 10(-11)-10(-13) M and association rate constants of 3 x 10(6)-5 x 10(6) M-1.s-1 [13].
  • Comparison with the X-ray structure of cystatin B in the papain complex shows that the conformation of the first binding loop is quite similar to that of cystatin A, with an rms deviation of 0.78 A for the backbone atoms in the 43-53 region (cystatin A numbering) [23].
  • The principal difference is the presence of two conformationally unrestricted regions in stefin A that form two of the components of the tripartite wedge which docks into the active site of the target proteinase [24].

Regulatory relationships of CSTA


Other interactions of CSTA

  • We previously reported that a potent protein kinase C activator, 12-O-tetradecanoylphorbol-13-acetate, increases human cystatin A expression by the activation of AP-1 proteins [16].
  • The approach of stefin A to cathepsin H induces structural changes along the interaction surface of both molecules, whereas no such changes were observed in the stefin B-papain complex [12].
  • The latter finding indicates that the intact N-terminal region serves as a guide directing cystatin A to the active site of cathepsin B, as has been proposed for cystatin C [26].
  • Stefin A is composed of 101 amino acids and has an Mr of 11 391 while stefin B contains 98 amino acids, has an Mr of 11 174 and is N-terminally blocked [14].
  • Consistent with these results, the MEK1 inhibitor, PD98059, further augmented 1,25(OH)(2)D3-induced cystatin A promoter activity and its expression [2].

Analytical, diagnostic and therapeutic context of CSTA


  1. The relationship of cathepsin B and stefin A mRNA localization identifies a potentially aggressive variant of human prostate cancer within a Gleason histologic score. Sinha, A.A., Quast, B.J., Korkowski, J.C., Wilson, M.J., Reddy, P.K., Ewing, S.L., Sloane, B.F., Gleason, D.F. Anticancer Res. (1999) [Pubmed]
  2. 1,25-dihydroxyvitamin D(3) increases human cystatin A expression by inhibiting the Raf-1/MEK1/ERK signaling pathway of keratinocytes. Takahashi, H., Ibe, M., Honma, M., Ishida-Yamamoto, A., Hashimoto, Y., Iizuka, H. Arch. Dermatol. Res. (2003) [Pubmed]
  3. Overexpression of stefin A in human esophageal squamous cell carcinoma cells inhibits tumor cell growth, angiogenesis, invasion, and metastasis. Li, W., Ding, F., Zhang, L., Liu, Z., Wu, Y., Luo, A., Wu, M., Wang, M., Zhan, Q., Liu, Z. Clin. Cancer Res. (2005) [Pubmed]
  4. Primary tumour expression of the cysteine cathepsin inhibitor Stefin A inhibits distant metastasis in breast cancer. Parker, B.S., Ciocca, D.R., Bidwell, B.N., Gago, F.E., Fanelli, M.A., George, J., Slavin, J.L., Möller, A., Steel, R., Pouliot, N., Eckhardt, B.L., Henderson, M.A., Anderson, R.L. J. Pathol. (2008) [Pubmed]
  5. Three-dimensional domain swapping in the folded and molten-globule states of cystatins, an amyloid-forming structural superfamily. Staniforth, R.A., Giannini, S., Higgins, L.D., Conroy, M.J., Hounslow, A.M., Jerala, R., Craven, C.J., Waltho, J.P. EMBO J. (2001) [Pubmed]
  6. Cysteine proteinase inhibitor cystatin A in breast cancer. Kuopio, T., Kankaanranta, A., Jalava, P., Kronqvist, P., Kotkansalo, T., Weber, E., Collan, Y. Cancer Res. (1998) [Pubmed]
  7. Properties of a plasma membrane-associated cathepsin B-like cysteine proteinase in metastatic B16 melanoma variants. Rozhin, J., Robinson, D., Stevens, M.A., Lah, T.T., Honn, K.V., Ryan, R.E., Sloane, B.F. Cancer Res. (1987) [Pubmed]
  8. Cysteine proteinase inhibitors stefin A, stefin B, and cystatin C in sera from patients with colorectal cancer: relation to prognosis. Kos, J., Krasovec, M., Cimerman, N., Nielsen, H.J., Christensen, I.J., Brünner, N. Clin. Cancer Res. (2000) [Pubmed]
  9. Immunohistochemical localization of cathepsin L and cystatin A in normal skin and skin tumors. Palungwachira, P., Kakuta, M., Yamazaki, M., Yaguchi, H., Tsuboi, R., Takamori, K., Ogawa, H. J. Dermatol. (2002) [Pubmed]
  10. Collision-induced dissociation spectra obtained by Fourier transform ion cyclotron resonance mass spectrometry using a 13C,15N-doubly depleted protein. Akashi, S., Takio, K., Matsui, H., Tate, S., Kainosho, M. Anal. Chem. (1998) [Pubmed]
  11. Decreased expression of filaggrin in atopic skin. Seguchi, T., Cui, C.Y., Kusuda, S., Takahashi, M., Aisu, K., Tezuka, T. Arch. Dermatol. Res. (1996) [Pubmed]
  12. 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. Jenko, S., Dolenc, I., Guncar, G., Dobersek, A., Podobnik, M., Turk, D. J. Mol. Biol. (2003) [Pubmed]
  13. Characterization by spectroscopic, kinetic and equilibrium methods of the interaction between recombinant human cystatin A (stefin A) and cysteine proteinases. Pol, E., Olsson, S.L., Estrada, S., Prasthofer, T.W., Björk, I. Biochem. J. (1995) [Pubmed]
  14. Differences in specificity for the interactions of stefins A, B and D with cysteine proteinases. Lenarcic, B., Krizaj, I., Zunec, P., Turk, V. FEBS Lett. (1996) [Pubmed]
  15. Pulmonary vascular resistance correlates in intact normal and abnormal canine lungs. Canada, E., Benumof, J.L., Tousdale, F.R. Crit. Care Med. (1982) [Pubmed]
  16. Expression of human cystatin A by keratinocytes is positively regulated via the Ras/MEKK1/MKK7/JNK signal transduction pathway but negatively regulated via the Ras/Raf-1/MEK1/ERK pathway. Takahashi, H., Honma, M., Ishida-Yamamoto, A., Namikawa, K., Kiyama, H., Iizuka, H. J. Biol. Chem. (2001) [Pubmed]
  17. Role of cathepsins and cystatins in patients with recurrent miscarriage. Nakanishi, T., Ozaki, Y., Blomgren, K., Tateyama, H., Sugiura-Ogasawara, M., Suzumori, K. Mol. Hum. Reprod. (2005) [Pubmed]
  18. Human cystatins in normal and diseased tissues--a review. Järvinen, M., Rinne, A., Hopsu-Havu, V.K. Acta Histochem. (1987) [Pubmed]
  19. Immunohistochemical staining of cathepsins B, L and stefin A in human hypophysis and pituitary adenomas. Strojnik, T., Lah, T.T., Zidanik, B. Anticancer Res. (2005) [Pubmed]
  20. Cathepsin L activity and its inhibitor in human otitis media. Kusunoki, T., Nishida, S., Murata, K., Kobashi, K., Nakatani, H., Hiwasa, T., Tomura, T. The Journal of otolaryngology. (2001) [Pubmed]
  21. Differences in the effects of TFE on the folding pathways of human stefins A and B. Zerovnik, E., Virden, R., Jerala, R., Kroon-Zitko, L., Turk, V., Waltho, J.P. Proteins (1999) [Pubmed]
  22. Hydrophobic sequences can substitute for the wild-type N-terminal sequence of cystatin A (stefin A) in tight binding to cysteine proteinases selection of high-affinity N-terminal region variants by phage display. Ylinenjärvi, K., Widersten, M., Björk, I. Eur. J. Biochem. (1999) [Pubmed]
  23. 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. Tate, S., Ushioda, T., Utsunomiya-Tate, N., Shibuya, K., Ohyama, Y., Nakano, Y., Kaji, H., Inagaki, F., Samejima, T., Kainosho, M. Biochemistry (1995) [Pubmed]
  24. Structural characterisation of human stefin A in solution and implications for binding to cysteine proteinases. Martin, J.R., Jerala, R., Kroon-Zitko, L., Zerovnik, E., Turk, V., Waltho, J.P. Eur. J. Biochem. (1994) [Pubmed]
  25. Human cathepsin F: expression in baculovirus system, characterization and inhibition by protein inhibitors. Fonovic, M., Brömme, D., Turk, V., Turk, B. Biol. Chem. (2004) [Pubmed]
  26. 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. Estrada, S., Nycander, M., Hill, N.J., Craven, C.J., Waltho, J.P., Björk, I. Biochemistry (1998) [Pubmed]
  27. Immunolocalization of human cystatins in neutrophils and lymphocytes. Davies, M.E., Barrett, A.J. Histochemistry (1984) [Pubmed]
  28. Prognostic value of cathepsins B, H, L, D and their endogenous inhibitors stefins A and B in head and neck carcinoma. Budihna, M., Strojan, P., Smid, L., Skrk, J., Vrhovec, I., Zupevc, A., Rudolf, Z., Zargi, M., Krasovec, M., Svetic, B., Kopitar-Jerala, N., Kos, J. Biol. Chem. Hoppe-Seyler (1996) [Pubmed]
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