Post-translational modifications

Cellular systems react to cellular signals within seconds, activating, or shutting down processes. This enormous speed cannot be accomplished by transcriptional or translational processes, as these processes are orders of magnitude slower. Post-translational modifications (PTMs) are modifications added after the synthesis of proteins. They are put on or taken off-target proteins by enzymes, which can themselves be regulated by post-translational modifications. PTMs fall in two larger groups, small modifiers, like phosphorylation, methylation or acetylation and protein-based modifiers. One of the most important post-translational protein-based modifiers is Ubiquitin and its relatives. Ubiquitination is involved in many cellular processes, including protein degradation at the proteasome, autophagy, cell cycle control, and inflammation.

Small post-translational modifications

The best-studied post-translational modifications so far are phosphorylations. A phosphorylation can be added to the side chain of an amino acid in ann enzymatic reaction and removed by a different enzyme. This allows the rapid regulation of proteins independent of transcription, translation and degradation. A small post-translational modification acts here like molecular switch (Figure 1).

In recent years other post-translational modifications like acetylations and methylations of arginines and lysines have gained more interest as these modifications are involved in post-translational regulation as well. The best-studied examples are the tails of the histone proteins. Here the addition of methylations regulates the folding of the chromatin and thus is regulating silencing events in the cell. 

The systematic analysis of post-translational modifications in large scale studies revealed that the modifications are not only appearing on histones but also on many other proteins like transcription factors. 

C/EBPß modifications and regulation of activity

The transcription factor family of C/EBP is involved in the regulation of many cellular processes from differentiation to tissue specific gene expression. The family consists of four members C/EBP alpha, beta, gamma and delta. In a joined effort with the Leutz laboratory at the Max-Delbrück Center in Berlin, we were able to identify more than 35 modifications on lysines and arginines in C/EBPß. These modifications are involved in the regulation of different processes. One example is the modification at position three (arginine) of the longest form of C/EBPß. Here we were able to show that the modification is directly involved in the recruitment of the SWI/SNF complex and regulates the downstream myeloid and adipogenic gene regulation. We were able to show the effect on differentiation using molecular mimics as shown in figure 2.