Part of the Springer Theses book series (Springer Theses)


The here presented crystallographic analysis of the murine cCP and iCP emphasizes the biological impact of subtle differences that are not predictable from sequence alignments and that can only be resolved by structural data. However, owing to the applied methodology, the results presented provide no insights into the dynamics of the 20S proteasome that might have substantial effects on substrate binding as well as enzyme inhibition.


Side Chain Conformation Cleavage Preference Protein Side Chain Amino Acid Network Leucine Side Chain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    H.G. Rammensee, T. Friede, S. Stevanovi, MHC ligands and peptide motifs: first listing. Immunogenetics 41, 178–228 (1995)CrossRefGoogle Scholar
  2. 2.
    M. Basler, M. Dajee, C. Moll, M. Groettrup, C.J. Kirk, Prevention of experimental colitis by a selective inhibitor of the immunoproteasome. J. Immunol. 185, 634–641 (2010)CrossRefGoogle Scholar
  3. 3.
    A.C. Mirabella, A.A. Pletnev, S.L. Downey, B.I. Florea, T.B. Shabaneh, M. Britton, M. Verdoes, D.V. Filippov, H.S. Overkleeft, A.F. Kisselev, Specific cell-permeable inhibitor of proteasome trypsin-like sites selectively sensitizes myeloma cells to bortezomib and carfilzomib. Chem. Biol. 18, 608–618 (2011)CrossRefGoogle Scholar
  4. 4.
    M. Groll, L. Ditzel, J. Löwe, D. Stock, M. Bochtler, H.D. Bartunik, R. Huber, Structure of 20S proteasome from yeast at 2.4 Å resolution. Nature 386, 463–471 (1997)CrossRefGoogle Scholar
  5. 5.
    M. Orlowski, C. Cardozo, C. Michaud (1993). Evidence for the presence of five distinct proteolytic components in the pituitary multicatalytic proteinase complex. Properties of two components cleaving bonds on the carboxyl side of branched chain and small neutral amino acids, Biochemistry, 32, 1563–1572 Google Scholar
  6. 6.
    W. Chen, C.C. Norbury, Y. Cho, J.W. Yewdell, J.R. Bennink, Immunoproteasomes shape immunodominance hierarchies of antiviral CD8(+) T cells at the levels of T cell repertoire and presentation of viral antigens. J. Exp. Med. 193, 1319–1326 (2001)CrossRefGoogle Scholar
  7. 7.
    E. Huber, M. Basler, R. Schwab, W. Heinemeyer, C.J. Kirk, M. Groettrup, M. Groll, Immuno- and constitutive proteasome crystal structures reveal differences in substrate and inhibitor specificity. Cell 148, 727–738 (2012)CrossRefGoogle Scholar
  8. 8.
    U. Seifert, L.P. Bialy, F. Ebstein, D. Bech-Otschir, A. Voigt, F. Schroter, T. Prozorovski, N. Lange, J. Steffen, M. Rieger, U. Kuckelkorn, O. Aktas, P.M. Kloetzel, E. Kruger, Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress. Cell 142, 613–624 (2010)CrossRefGoogle Scholar
  9. 9.
    P. Deol, D.M. Zaiss, J.J. Monaco, A.J. Sijts, Rates of processing determine the immunogenicity of immunoproteasome-generated epitopes. J. Immunol. 178, 7557–7562 (2007)Google Scholar
  10. 10.
    R.E. Toes, A.K. Nussbaum, S. Degermann, M. Schirle, N.P. Emmerich, M. Kraft, C. Laplace, A. Zwinderman, T.P. Dick, J. Muller, B. Schonfisch, C. Schmid, H.J. Fehling, S. Stevanovic, H.G. Rammensee, H. Schild, Discrete cleavage motifs of constitutive and immunoproteasomes revealed by quantitative analysis of cleavage products. J. Exp. Med. 194, 1–12 (2001)CrossRefGoogle Scholar
  11. 11.
    M. Gaczynska, K.L. Rock, T. Spies, A.L. Goldberg, Peptidase activities of proteasomes are differentially regulated by the major histocompatibility complex-encoded genes for LMP2 and LMP7. Proc. Natl. Acad. Sci. U S A 91, 9213–9217 (1994)CrossRefGoogle Scholar
  12. 12.
    C. Blackburn, K.M. Gigstad, P. Hales, K. Garcia, M. Jones, F.J. Bruzzese, C. Barrett, J.X. Liu, T.A. Soucy, D.S. Sappal, N. Bump, E.J. Olhava, P. Fleming, L.R. Dick, C. Tsu, M.D. Sintchak, J.L. Blank, Characterization of a new series of non-covalent proteasome inhibitors with exquisite potency and selectivity for the 20S beta5-subunit. Biochem. J. 430, 461–476 (2010)CrossRefGoogle Scholar
  13. 13.
    H.J. Fehling, W. Swat, C. Laplace, R. Kuhn, K. Rajewsky, U. Muller, H. von Boehmer, MHC class I expression in mice lacking the proteasome subunit LMP-7. Science 265, 1234–1237 (1994)CrossRefGoogle Scholar
  14. 14.
    L. Tu, C. Moriya, T. Imai, H. Ishida, K. Tetsutani, X. Duan, S. Murata, K. Tanaka, C. Shimokawa, H. Hisaeda, K. Himeno, Critical role for the immunoproteasome subunit LMP7 in the resistance of mice to Toxoplasma gondii infection. Eur. J. Immunol. 39, 3385–3394 (2009)CrossRefGoogle Scholar
  15. 15.
    M. Groettrup, C.J. Kirk, M. Basler, Proteasomes in immune cells: more than peptide producers? Nat. Rev. Immunol. 10, 73–78 (2010)CrossRefGoogle Scholar
  16. 16.
    L. Van Kaer, P.G. Ashton-Rickardt, M. Eichelberger, M. Gaczynska, K. Nagashima, K.L. Rock, A.L. Goldberg, P.C. Doherty, S. Tonegawa, Altered peptidase and viral-specific T cell response in LMP2 mutant mice. Immunity 1, 533–541 (1994)CrossRefGoogle Scholar
  17. 17.
    M. Basler, J. Moebius, L. Elenich, M. Groettrup, J.J. Monaco, An altered T cell repertoire in MECL-1-deficient mice. J. Immunol. 176, 6665–6672 (2006)Google Scholar
  18. 18.
    E.M. Huber, M. Groll, Inhibitors for the immuno- and constitutive proteasome: current and future trends in drug development. Angew. Chem. Int. Ed. Engl. 51, 8708–8720 (2012)CrossRefGoogle Scholar
  19. 19.
    T. Muchamuel, M. Basler, M.A. Aujay, E. Suzuki, K.W. Kalim, C. Lauer, C. Sylvain, E.R. Ring, J. Shields, J. Jiang, P. Shwonek, F. Parlati, S.D. Demo, M.K. Bennett, C.J. Kirk, M. Groettrup, A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis. Nat. Med. 15, 781–787 (2009)CrossRefGoogle Scholar
  20. 20.
    H.T. Ichikawa, T. Conley, T. Muchamuel, J. Jiang, S. Lee, T. Owen, J. Barnard, S. Nevarez, B.I. Goldman, C.J. Kirk, R.J. Looney, J.H. Anolik, Novel proteasome inhibitors have a beneficial effect in murine lupus via the dual inhibition of type i interferon and autoantibody secreting cells. Arthritis Rheum. 64, 493–503 (2011)CrossRefGoogle Scholar
  21. 21.
    Y. Nagayama, M. Nakahara, M. Shimamura, I. Horie, K. Arima, N. Abiru, Prophylactic and therapeutic efficacies of a selective inhibitor of the immunoproteasome for Hashimoto's thyroiditis, but not for graves hyperthyroidism, in mice. Clin. Exp. Immunol., 168, 268–273 (2012)Google Scholar
  22. 22.
    M. Groll, R. Huber, B.C. Potts, Crystal structures of Salinosporamide A (NPI-0052) and B (NPI-0047) in complex with the 20S proteasome reveal important consequences of beta-lactone ring opening and a mechanism for irreversible binding. J. Am. Chem. Soc. 128, 5136–5141 (2006)CrossRefGoogle Scholar
  23. 23.
    E.J. Corey, W.D. Li, Total synthesis and biological activity of lactacystin, omuralide and analogs. Chem. Pharm. Bull. 47, 1–10 (1999)CrossRefGoogle Scholar
  24. 24.
    M. Nett, T.A. Gulder, A.J. Kale, C.C. Hughes, B.S. Moore, Function-oriented biosynthesis of beta-lactone proteasome inhibitors in Salinispora tropica. J. Med. Chem. 52, 6163–6167 (2009)CrossRefGoogle Scholar
  25. 25.
    S.D. Demo, C.J. Kirk, M.A. Aujay, T.J. Buchholz, M. Dajee, M.N. Ho, J. Jiang, G.J. Laidig, E.R. Lewis, F. Parlati, K.D. Shenk, M.S. Smyth, C.M. Sun, M.K. Vallone, T.M. Woo, C.J. Molineaux, M.K. Bennett, Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 67, 6383–6391 (2007)CrossRefGoogle Scholar
  26. 26.
    M. Groll, C.R. Berkers, H.L. Ploegh, H. Ovaa, Crystal structure of the boronic acid-based proteasome inhibitor bortezomib in complex with the yeast 20S proteasome. Structure 14, 451–456 (2006)CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.Chair of BiochemistryTechnische Universität MünchenGarchingGermany

Personalised recommendations