Project Details
Projekt
NEDD8: Mechanisms of conjugation and identification of binding partners
Applicant
Professor Dr. Martin Scheffner
Subject Area
Cell Biology
Term
from 2008 to 2014
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 72025282
Genetic studies in mice have shown that the RING domain protein Mdm2 is a major antagonist of the tumor suppressor p53. At the biochemical level, Mdm2 functions as both an E3 ubiquitin-protein ligase and E3 NEDD8-protein ligase for p53 thereby regulating subcellular localization, stability, and the transcriptional transactivation properties of p53. However, while ubiquitylation of p53 has been extensively studied by many groups, only little is known about the mechanisms involved in Mdm2- mediated neddylation of p53 as well as the mechanism, by which neddylation affects p53 function. In the current funding period, we have identified the Mdm2-related protein MdmX as a substrate for Mdm2-mediated neddylation and showed that the previously uncharacterized protein NCE2 is a NEDD8-conjugating enzyme. In this application, we propose to continue our efforts to identify proteins that are involved in Mdm2-mediated neddylation of p53 and MdmX and to obtain insight into the mechanisms that determine whether Mdm2 induces ubiquitylation or neddylation of associated proteins. In addition, the NEDD8-conjugating enzymes NCE2 and UBC12 will be functionally further characterized and affinity-based purification approaches will be employed to identify proteins that selectively bind to and eventually determine the fate of neddylated proteins. Taken together, the proposed studies will contribute to the elucidation of the mechanisms involved in Mdm2-mediated neddylation in particular and in neddylation of proteins in general.
DFG Programme
Priority Programmes
