State of the art in (semi-)synthesis of Ubiquitin- and Ubiquitin-like tools.

Protein ubiquitination is a key post-translational modification in regulating many fundamental cellular processes and dysregulation of these processes can give rise to a vast array of diseases. Unravelling the molecular mechanisms of ubiquitination hence is an important area in current ubiquitin research with as aim to understand this enigmatic process. The complexity of ubiquitin (Ub) signaling arises from the large variety of Ub conjugates, where Ub is attached to other Ub proteins, Ub-like proteins, and protein substrates. The chemical preparation of such Ub conjugates in high homogeneity and in adequate amounts contributes greatly to the deciphering of Ub signaling. The strength of these chemically synthesized conjugates lies in the chemo-selectivity in which they can be created that are sometimes difficult to obtain using biochemical methodology. In this review, we will discuss the progress in the chemical protein synthesis of state-of-the-art Ub and Ub-like chemical probes, their unique concepts and related discoveries in the ubiquitin field.