2019/03/07
TUBEs, SUBES and beyond: Molecular traps for the study of proteins modified by Ubiquitin or Ubiquitin-like molecules.
Post-translational protein modifications by members of the Ubiquitin family has become an intense area of research as it is implicated in many biological processes and diseases, e.g. cancer and neurodegeneration.
Ubiquitin-like proteins (UbL) can modify substrate proteins and change their fate. UbLs can in turn be modified, forming chains of high complexity that might have different outcomes in the cells. The diverse and enigmatic information contained in these single and chain-type modifications is called the “Ubiquitin Code”. Many questions remain to be answered in this field: How are these chains formed? How are they recognized? What is their function? How are they altered in diseases? In recent years, the development of new tools has been instrumental to impulse the study of this subject of research. Among them, tandem-repeated Ubiquitin binding entities, TUBEs, together with their close relatives SUBEs (Small Ubiquitin-like Modifier- SUMO- binding entities), allowed the identification and characterization of proteins modified by UbL chains and the protein partners implicated in their formation and function.
Patented and licensed by CIC bioGUNE, TUBEs and SUBEs have been extensively used in multiple experimental settings, such as ubiquitylation studies of specific proteins, mass spectrometry analysis of modified proteins under different stimuli, and the development of new detection methods for ubiquitylated substrates. Emerging applications for these tools include high-throughput screening and drug discovery.
A recently published review in the journal Trends in Biochemical Sciences (TIBS) collects all pertinent information on uses and applications of TUBEs and derived technologies in different fields of research. Published examples would be the analysis of K63-Ubiquitin chains in mitophagy, HIF1A ubiquitylation signaling degradation by the autophagy–lysosome system, or the accumulation of ubiquitylated p53 in response to chemotherapy, among other applications. Development of new technologies based in other binding strategies, like peptide aptamers- affimers, adnectins or monobodies, darpins- or nanobodies, is also discussed. TUBES and SUBES, together with related techniques, will contribute to unraveling the secrets of the Ubiquitin Code in the next few years.
Reference:
Mattern M, Sutherland J, Kadimisetty K, Barrio R, Rodriguez MS. 2019. Using Ubiquitin Binders to Decipher the Ubiquitin Code. Trends Biochem Sci. pii: S0968-0004(19)30020-9.
Figure Caption
Schematic representation of molecular traps for the binding of proteins modified by Ubiquitin-like molecules. Abbreviations: Ub, ubiquitin; SU, SUMO, small Ub-like modifier; UBD, Ubiquitin binding domains; SIM, SUMO interacting motifs, UbL, Ub-like protein; G, glycine; K, lysine.
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