Print Page  

Ubiquitin-dependent cell signaling

Silke Wiesner

Silke Wiesner

  • PhD at the EMBL Heidelberg, 1998-03
  • Postdoctoral research at the Hospital for Sick Children, 
    University of Toronto, 2003-08
  • Max Planck research group leader at the MPI since 2008
  • 2017: moving to University of Regensburg

Research Interest

Many proteins function in the cell only at specific subcellular locations and for a limited amount of time. Proteins that are no longer required by the cell get modified with a small protein called Ubiquitin that tags them for degradation. This reaction is catalyzed by the sequential action of an E1, an E2 and a Ubiquitin ligating (E3) enzyme. Ubiquitination represents not only one of the most common, but is also one of the structurally most complex protein modifications to have been described. This structural complexity is reflected in the wide array of functions that ubiquitination has in the cell. Not surprisingly, aberrant ubiquitination enzyme function gives rise to severe cellular dysfunctions that cause numerous human diseases including cancer.

Using NMR spectroscopy, X-ray crystallography and functional assays, our group seeks to unravel the molecular mechanism underlying protein ubiquitination and to understand how ubiquitin-modification of proteins regulates cellular processes. We are particularly interested in the structure, function, and regulation of Ubiquitin ligases, as these enzymes are the first in the reaction chain to physically interact with the target protein and thus confer specificity to the ubiquitination reaction. Among the proteins that we are studying are the HECT-type Ubiquitin ligases Smurf2, its cognate E2 enzyme UbcH7 and Ubiquitin itself.


Selected Reading

1) Wiesner S*, Wybenga-Groot LE*, Warner N, Lin H, Pawson T, et al. (2006) A change in conformational dynamics underlies the activation of Eph receptor tyrosine kinases. EMBO J 25, 4686-96. *equal contribution

2) Wiesner S, Ogunjimi AA, Wang HR, Rotin D, Sicheri F, et al. (2007) Autoinhibition of the HECT-type ubiquitin ligase Smurf2 through its C2 domain. Cell 130, 651-62.

3) Ogunjimi AA*, Wiesner S*, Briant DJ, Varelas X, Sicheri F, et al. (2010) The ubiquitin binding region of the Smurf HECT domain facilitates polyubiquitylation and binding of ubiquitylated substrates. J Biol Chem 285, 6308-15. *equal contribution
(click to enlarge)
Cartoon representation of reaction intermediates formed by HECT-type Ubiquitin ligases (Left panel). Question marks highlight the unknown mechanisms of Ubiquitin (Ub) transfer from the E2 via the HECT domain to the target protein. Right panel: Structural model of the Smurf2 HECT domain (green) in complex with UbcH7 (E2; blue). The catalytic cysteines (yellow) are separated by 47 Å (black line) and thus too remote to provide an explanation for Ubiquitin transfer.