Structure and Function of Tripeptidyl Peptidase II, a Giant Cytosolic Protease
Tripeptidyl peptidase II is the largest known eukaryotic peptidase. It has been described as a ‘multi-purpose peptidase’, which, in addition to its house-keeping function in intracellular protein degradation, plays a role in several vital cellular processes such as cell division, apoptosis or antigen processing. Under conditions where the function of the proteasome is compromised, but also in certain diseases, like muscle wasting and cancer, TPPII is upregulated. A number of studies have been performed to reveal its role in health and disease states, but although many functions have been ascribed to TPPII, its substrates or reaction partners have remained obscure.
TPPII is a homooligomer with an unusual structure: Two strands composed of stacked dimers are wound into a large complex (5-6 MDa) with a spindle-like shape. When not assembled, TPPII dimers have minimal activity, full activity is only found in the assembled complex. Combining cryo electron microscopy, X-ray crystallography, homology modelling and flexible fitting, we have obtained hybrid models for human and Drosophila TPPII. The active sites of TPPII are buried inside a cavity system and the entries to this system are framed by structures strongly resembling tetratricopeptide repeats. These domains may mediate interactions with substrates or other proteins of the catabolic pathway. Our current investigations are focused on the identification of substrates and interaction partners of TPPII as well as on structural studies of TPPII homologues from other organisms.
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Chuang C.K., Rockel B., Seyit G., Walian P.J., Schönegge A.M., Peters J., Zwart P.H., Baumeister W., Jap B.K.: Hybrid Molecular Structure of the Giant Protease Tripeptidyl Peptidase II. Nature Structural & Molecular Biology 17: 990-996, 2010
Rockel B. and Baumeister W.: A Tale of Two Giant Proteases. Ernst Schering Found Symp Proc (1):17-40, 2008
Baumeister W. and Rockel B.: Molekulare Maschinen in 3D. Labor & More 04/07: 36-37, 2007
Seyit G., Rockel B., Baumeister W. and Peters J.: Size matters: The spindle-shaped 6 MDa Tripeptidylpeptidase II complex from Drosophila melanogaster stabilizes the activated state. Journal of Biological Chemistry 281: 25723-25733, 2006
Rockel B., Peters J., Müller S.A., Seyit G., Ringler P., Hegerl R., Glaeser R.M. and Baumeister W.: Molecular architecture and assembly mechanism of Drosophila Tripeptidyl peptidase II. Proceedings of the National Academy of Sciences of the United States of America 102: 10135-10140, 2005
Rockel B., Bosch J. and Baumeister W.: Structural studies of large self-compartmentalizing proteases, in: Protein Degradation: The Ubiquitin-Proteasome System Vol. 2: pp. 183-214 (Mayer, R.J., Ciechanover, A.J.,Rechsteiner, M., Eds.) Wiley-VCH, 2005
Adiga U., Baxter W.T., Hall R.J., Rockel B., Rath B., Frank J. and Glaeser R.M.: Particle Picking by Segmentation: A comparative Study with SPIDER-based manual particle picking. Journal of Structural Biology 125: 211-220, 2005
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