Universität zu Köln 

Prof. Dr. Thorsten Hoppe

Institut für Genetik/CECAD Forschungszentrum, Universität zu Köln
email: thorsten.hoppe@uni-koeln.de
phone: +49-(0)221 478-84218
website

The ubiquitin/proteasome system is pivotal for the elimination of misfolded proteins, and defects in this pathway can result in the pathogenesis of diseases such as skeletal muscle atrophy. Besides the already known E1, E2 and E3 enzymes, which are catalysts for substrate ubiquitylation, additional polyubiquitin chain elongation factors have been identified and named E4. Our recent work revealed a novel mechanism in which two E3 enzymes, CHN-1 and UFD-2, team up to achieve E4-like polyubiquitylation in Caenorhabditis elegans. We have shown that the assembly of this E3 complex is controlled by tissue specific co-expression of both E3 enzymes in a developmentally-regulated manner, which is important for proteasomal degradation of the myosin-specific chaperone UNC-45. The combination of different E3 enzymes offers the possibility to form alternative ubiquitylation complexes that mediate substrate specificity. In fact, beside its role in myosin assembly, CHN-1 forms a homo dimer cooperating with molecular chaperones in protein quality control or alternatively interacts with the C. elegans Parkin homolog PDR-1, an E3 enzyme, in ER homeostasis. The central objective of our proposed research is to identify mechanistic and developmental aspects of protein degradation pathways defined by alternative combinations of E3 enzymes. The detailed analysis of binding partners and substrate-ubiquitylation combined with structural data will help to decipher how substrate recruitment and ubiquitin chain formation are determined by specific homo- or heterooligomeric E3 ligase complexes.

Running time: 07/2011 – 06/2015

Recent publications:

Gazda, L., Pokrzywa, W., Hellerschmied, D., Löwe, T., Forné, I., Mueller-Planitz, F., Hoppe, T., and Clausen, T. (2013). The myosin chaperone UNC-45 is organized in tandem modules to support myofilament formation in C. elegans. Cell. 152, 183-95. PubMed

Pokrzywa, W. and Hoppe, T. (2013). Chaperoning myosin assembly in muscle formation and aging. Worm 2:3, 1-4. Landesbioscience

Franz, A., Orth M., Pirson P.A., Sonneville R., Blow J.J., Gartner A., Stemmann O., Hoppe T. (2011). CDC-48/p97 coordinates CDT-1 degradation with GINS chromatin dissociation to ensure faithful DNA replication. Mol Cell. 44, 85-96.

Kuhlbrodt, K., Janiesch, P.C., Kevei, E., Segref, A., Barikbin, R., and Hoppe T. (2011). The Machado-Joseph disease deubiquitylase ATX-3 couples longevity and proteostasis. Nat. Cell Biol. 13, 273-281.

Kim, J., Löwe, T., and Hoppe T. (2008). Protein quality control gets muscle into shape. Trends Cell Biol. 18, 264-72.

Janiesch, P.C., Kim, J., Mouysset, J., Barikbin, R., Lochmüller, H., Cassata, G., Krause, S., and Hoppe T. (2007). The ubiquitin-selective chaperone CDC-48/p97 links myosin assembly to human myopathy. Nat. Cell Biol. 9, 379-90.

Landsverk, M.L., Hutagalung, A.H., Li, S., Najafov, A., Hoppe T., Barral, J.M., and Epstein, H.F. (2007). The UNC-45 chaperone mediates sarcomere assembly through myosin degradation in C. elegans. J. Cell Biol. 177, 205-10.

Springer, W., Hoppe T., Schmidt, E., and Baumeister, R. (2005). A Caenorhabditis elegans Parkin mutant with altered solubility couples ?-synuclein aggregation to proteotoxic stress. Hum. Mol. Genet. 14, 3407-23.

Hoppe T. (2005). Multiubiquitylation by E4 enzymes: one size doesn't fit all. Trends Biochem. Sci. 30, 183-187.

Hoppe T., Cassata, G., Barral, J.M., Springer, W., Hutagalung, A.H., Epstein, H.F., and Baumeister, R. (2004). Regulation of the myosin-directed chaperone UNC-45 by a novel E3/E4-multiubiquitylation complex in C. elegans. Cell 118, 337-49.

Koegl, M., Hoppe T., Schlenker, S., Ulrich, H.D., Mayer, T.U., and Jentsch, S. (1999). A novel ubiquitination factor, E4, is involved in multiubiquitin chain assembly. Cell 96, 635-644.