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Regulation of Ubiquitination

Background

Ubiquitin is a Nobel Prize winning posttranslational protein modifier. The postranslational modification of proteins with the small protein called ubiquitin is a crucial step in a diverse subset of different cellular regulatory mechanisms. The best described function of ubiquitination is the subsequent degradation of modified proteins by either the 26S proteasome or the vacuole/lysosome. Abberations in these important mechanisms lead to severe diseases ranging from cancer to neurodegeneration. The attachment of ubiquitin to target proteins is therefore a highly regulated process. It is regulated by an enzymatic reaction cascade: First, ubiquitin gets activated and attached to a internal cysteine residue within the ubiquitin acivating enzyme (E1); second the activated ubiquitin is transferred to a internal cysteine of a ubiquitin conjugating enzyme (E2) and finally ubiquitin ligases (E3) allow either the direct transfer of ubiquitin to a lysine residue of a substrate protein (A) or are first kept on an E3 internal cysteine residue (B). By further modification of lysine residues within the ubiquitin molecule so called polyubiquitin chains are build up. An interesting aspect of this reaction is the fact that ubiquitin has six internal lysine residues that can all be modified by ubiquitin to form polyubiquitin chains. This allows a huge variety of different regulatory steps. 

 

The Gid/CTLH complex

Addition of glucose to gluconeogenetic yeast cells leads to rapid ubiquitination and proteasomal degradation of the gluconeogenetic regulatory enzymes fructose-1,6-bisphosphatase (FBPase), phosphoenolpyruvate carboxykinase (PEPCK) and cytoplasmic malate dehydrogenase (MDH2). The responsible ubiquitin-ligase-complex (Gid-complex) consists of six core subunits (Gid1, Gid2, Gid5, Gid7, Gid8, Gid9). Gid2 and Gid9 contain ubiquitin-ligase (E3) typical RING finger domains. For E3 activation and subsequent substrate polyubiquitination an additional protein (Gid4) is synthesized after glucose addition and degraded by the Gid core complex thereafter. 

In higher organisms six highly conserved Gid-complex proteins are part of a protein complex with unknown function. Mammals have two Gid2/Rmd5 isoforms, RMND5a and RMND5b, while lower vertebrates only have one. In Xenopus laevis RMD5 is also part of a high-molecular-mass protein complex and the protein polyubiquitinates itself in vitro. This effect is dependent on its highly conserved noncanonical RING domain. We hypothesize that substrates other than the above mentioned exist in higher vertebrates. Therefore we plan to elucidate the functions of differing Gid/CTLH-complex subunits and the resulting substrate variation using yeast genetics, molecular biological methods and quantitative proteomics (DIGE). 

 

Available Research Positions

We are recruiting motivated MSc students, PhD students specifically interested in various topics involving ubiquitin. Complete applications including CV, certificates, research abstracts / list of publications and the names, phone and E-mail addresses of 1-2 academic referees should be send by E-mail.

 

 

Direktor:
Prof. Dr. Guido Posern

Abt. Ubiquitination: 
Leiter: Thorsten Pfirrmann 
Telefon: (0345) 557-3802 
Fax:        (0345) 557-3804 
Email:    Thorsten Pfirrmann

Hausanschrift:
Institut für Physiologische Chemie
Hollystrasse 1
06114 Halle (Saale)

Sekretariat:
Frau Liebert-Hoang
Telefon: (0345) 557-3812 
Fax:        (0345) 557-3811
Email:   Sekretariat