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MPI für Biochemie  

Molecular Structural Biology
Wolfgang Baumeister

Tripeptidyl Peptidase II

 

Members

Dr. Beate Rockel

Phone: +49 - 89 - 8578 2698

Collaborations

Prof. Dr. Robert M. Glaeser & Dr. Dieter Typke

LBNL Berkeley, USA

 

Dr. Bing K. Jap & Dr. Peter J. Walian

LBNL Berkeley, USA

A giant protease with a twist

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Cytosolic protein degradation proceeds mainly via large, self-compartmentalized protein complexes burying their active sites in a secluded compartment. The paradigm for such a complex is the 26S proteasome, which degrades ubiquitinated proteins in an ATP-dependent manner. In the successive processing of the resulting, relatively small products, large complexes are also involved. One such large complex is tripeptidyl peptidase II (TPPII), an aminopeptidase of the subtilisin-type of serine proteases, which cleaves tripeptides from the free N-terminus of oligopeptides.

In recent years, TPPII has gained particular attention because of its up-regulation in mammalian cells in the presence of proteasome-inhibitors and its reported capability of substituting for some metabolic functions of the proteasome. In addition, TPPII has been implicated in the MHC class I processing, in diseases that are based on increased or uncontrolled proteolysis such as in septic muscles or in malignant cells, and recently also in fat-metabolism. A more specialized task is carried out by a membrane-bound TPPII variant, which inactivates cerebral neurotransmitters.

 

Having a molecular mass of 6 MDa, Drosophila TPPII is one of the largest eukaryotic protease complexes known. It is a 40-mer of 150 kDa subunits, which are assembled into a spindle-shaped 28 x 60-nm particle consisting of two segmented and twisted strands. This spindle structure of TPPII ensures high activity at high stability and presumably is the structural basis for self-compartmentalisation and protein-protein interactions.

 

We are interested in the molecular mechanism of TPPII and employ electron cryo-microscopy, xray-crystallography, biochemistry and molecular biology to solve its structure and to study its molecular interactions.

 

Publications

  1. C.K. Chuang, B. Rockel, G. Seyit, P.J. Walian, A.-M. Schönegge, J. Peters, P.H. Zwart, W. Baumeister, B. K. Jap (2010) Hybrid Molecular Structure of the Giant Protease Tripeptidyl Peptidase II. Nature Structural & Molecular Biology 17: 990-996
  2. B. Rockel, W. Baumeister (2008) A Tale of Two Giant Proteases. Ernst Schering Found Symp Proc (1):17-40
  3. W. Baumeister, B. Rockel (2007) Molekulare Maschinen in 3D. Labor & More 04/07: 36-37.
  4. G. Seyit, B. Rockel, W. Baumeister, J. Peters (2006) Size matters: The spindle-shaped 6 MDa Tripeptidylpeptidase II complex from Drosophila melanogaster stabilizes the activated state. Journal of Biological Chemistry 281: 25723-25733.
  5. B. Rockel, J. Peters, S. A. Müller, G. Seyit, P. Ringler, R. Hegerl, R. M. Glaeser, W. Baumeister (2005) 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.
  6. B. Rockel, J. Bosch, W. Baumeister (2005) 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.
  7. U. Adiga, W. T. Baxter, R. J. Hall, B. Rockel, B. Rath, J. Frank, R. M. Glaeser (2005) Particle Picking by Segmentation: A comparative Study with SPIDER-based manual particle picking. Journal of Structural Biology 125: 211-220.
  8. B. Rockel, J. Peters, B. Kühlmorgen, R. M. Glaeser, W. Baumeister (2002) A giant protease with a twist: the TPP II complex from Drosophila studied by electron microscopy. Embo J. 21: 5979-5984.