Plenary Speaker

Intracellular Proteolysis, Basic Science and Application
Robert Huber
Germany


Within cells or subcellular compartments misfolded and/or short-lived regulatory proteins are degraded by protease machines, cage-forming multi-subunit assemblages. Their proteolytic active sites are sequestered within the particles and located on the inner walls. Access of protein substrates is regulated by protein subcomplexes or protein domains which may assist in substrate unfolding dependent of ATP. Five protease machines will be described displaying different subunit structures, oligomeric states, enzymatic mechanisms, and regulatory properties.

Proteasome

Groll, M., Ditzel, L., Löwe, J., Stock, D., Bochtler, M., Bartunik, H. D. and Huber, R. (1997) Structure of 20S proteasome from yeast at 2.4 Å resolution. Nature 386, 463-471.

Groll, M., Heinemeyer, W., Jäger, S., Ullrich, T., Bochtler, M., Wolf, D. H. and Huber, R. (1999) The catalytic sites of 20S proteasomes and their role in subunit maturation: A mutational and crystallographic study. Proc. Natl. Acad. Sci. USA 96, 10976-10983.

Groll, M., Bajorek, M., Köhler, A., Moroder, L., Rubin, D. M., Huber, R., Glickman, M. H. and Finley, D. (2000) A gated channel into the proteasome core particle. Nature Struct. Biol. 7, 1062-1067.

Groll, M., Schellenberg, B., Bachmann, A. S., Archer, C. R., Huber, R., Powell, T. K., Lindow, S., Kaiser, M. and Dudler, R. (2008) A plant pathogen virulence factor inhibits the eukaryotic proteasome by a novel mechanism. Nature 452, 755-758.

HslV/HslU

Bochtler, M., Hartmann, C., Song, H. K., Bourenkov, G., Bartunik, H. and Huber, R. (2000) The structure of HslU and the ATP-dependent protease HslU-HslV. Nature 403, 800-805.

Song, H. K., Hartmann, C., Ramachandran, R., Bochtler, M., Behrendt, R., Moroder, L. and Huber, R. (2000) Mutational studies on HslU and its docking mode with HslV. Proc. Natl. Acad. Sci. USA 97, 14103-14108.

Ramachandran, R., Hartmann, C., Song, H. J., Huber, R. and Bochtler, M.(2002) Functional interactions of HslV(ClpQ) with the ATPase HslU(ClpY). Proc. Natl. Acad. Sci. USA 99, 7396-7401.

Tricorn

Brandstetter, H., Kim, J. S., Groll, M. and Huber, R. (2001) Crystal structure of the tricorn protease reveals a protein disassembly line. Nature 414, 466-470.

Kim, J. S., Groll, M., Musiol, H. J., Behrendt, R., Kaiser, M., Moroder, L., Huber, R. and Brandstetter H. (2002) Navigation inside a protease: substrate selection and product exit in the tricorn protease from Thermoplasma acidophilum. J. Mol. Biol. 324, 1041-1050.

Goettig, P., Groll, M., Kim, J. S., Huber, R. and Brandstetter, H. (2002) Structures of the tricorn interacting aminopeptidase F1 with different ligands explain its catalytic mechanism. EMBO J. 21, 5343-5352.

Dipeptidyl peptidase IV

Engel, M., Hoffmann, T., Wagner, L., Wermann, M., Heiser, U., Kiefersauer, R., Huber, R., Bode, W., Demuth, H. U. and Brandstetter, H. (2003) The crystal structure of dipeptidyl peptidase IV (CD26) reveals its functional regulation and enzymatic mechanism.Proc. Natl. Acad. Sci. USA 100, 5063-5068.

DegP(HtrA)

Krojer, T., Garrido-Franco, M., Huber, R., Ehrmann, M., and Clausen, T. (2002) Crystal structure of DegP (HtrA) reveals a new protease-chaperone machine. Nature 416, 455-459.

Krojer, T., Pangerl, K., Kurt, J., Sawa, J., Stingl, C., Mechtler, K., Huber, R., Ehrmann, M. and Clausen, T. (2008). Interplay of PDZ and protease domain of DegP ensures efficient elimination of misfolded proteins. Proc. Natl. Acad. Sci. USA 105, 7702-7707.

Krojer, T., Sawa, J., Schäfer, E., Saibil, H. R, Ehrmann, M, and Clausen, T. (2008).

http://www.ncbi.nlm.nih.gov/pubmed/18496527?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum
Structural basis for the regulated protease and chaperone function of DegP.

Nature 453, 885-890.