With the multitude of substrates targeted, and the myriad processes involved, it is not surprising that aberrations in the pathway are implicated in the pathogenesis of many diseases, certain malignancies and neuro-degeneration among them. Degradation of a protein via the ubiquitin/proteasome pathway involves two successive steps: (a) conjugation of multiple ubiquitin moieties to the substrate, and (b) degradation of the tagged protein by the downstream 26S proteasome complex. Despite intensive research, the unknown still exceeds what we currently know on intracellular protein degradation, and major key questions remain unsolved. Among these are the modes of specific and timed recognition for the degradation of the many substrates, and the mechanisms that underlie aberrations in the system that lead to pathogenesis of diseases.
The recent discovery of modification by ubiquitin-like proteins along with identification of “non-canonical” polyubiquitin chains that serve non-proteolytic functions, have broadened the scope of the system beyond proteolysis and set new challenges in for biologists and proteomic experts. Major challenges in the field are clearly (i) identification of the cellular proteins tagged by ubiquitin and ubiquitin-like proteins, (ii) identification of the downstream elements recognized by these chains, and (iii) deciphering the structure of the different ubiquitin and ubiquitin-like chains that tag the different proteins.