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UbiQ-news: Recent Scientific Accomplishments


Farid El Oualid


8 September 2020

Recent Scientific Accomplishments

First of all, we wish all of our customers and partners well during this COVID-19 pandemic.
Below we have listed some recent publications in which
UbiQ participated and that might be of interest to you.

As part of collaborative research carried out by The Netherlands Cancer Institute, Leiden University Medical Centre, Utrecht University, UbiQ and the University of Cologne, Hameed et al. report in Frontiers in Chemistry the synthesis of diubiquitin chains with a fully 15N-labeled distal ubiquitin. Advanced NMR spectroscopy was used to confirm that diubiquitin proteins adopt different conformations in solution. This structural flexibility is important in binding with ubiquitin-binding domains (UBD) thereby inducing unique responses. One of the well-known but poorly understood UBD-Ub interactions is the recognition of K6 linked ubiquitin chains by the ubiquitin-associated (UBA) domain of UBXN1 in the BRCA-mediated DNA repair pathway. Using 15N-labeled K6 diubiquitin, the C-terminally extended UBA domain of UBXN1 was shown to confer specificity to K6 diubiquitin while the non-extended version of the domain does not show any linkage preference. Thus, the two distinct conformations of K6 diubiquitin that exist in solution converge into a single conformation upon binding to the UBA domain of the UBXN1 protein. It is likely that more of such extended UBA domains exist in nature and can contribute to linkage-specificity in ubiquitin signaling. 

As part of collaborative research between The Netherlands Cancer Institute, Leiden University Medical Centre, UbiQ and the University of Amsterdam, van Kruijsbergen et al. report in Frontiers in Chemistry detailed protocols for the development of antibodies recognizing site-specific ubiquitin modifications. The report describes considerations for antigen design (see also our UbiQ Block technology), screening and quality control experiments.

Collaborative research between the University of York, University of Glasgow and UbiQ looks into the (essential) roles of ubiquitin proteases (DUBs) and ubiquitin conjugation in Leishmania parasites. Leishmaniasis is a neglected tropical disease caused by parasites of the genus Leishmania. This disease, which has a tropical and sub-tropical distribution, is transmitted by the bite of a sandfly and causes around 70,000 deaths annually. Leishmania parasites need a variety of protein degradation pathways to allow the parasite to transition through the various life cycle stages that occur in its insect and mammalian hosts. Damianou et al. report on the use of activity-based protein profiling (using probes Cy5-Ub-PA, UbiQ-072 and Ub-PA, UbiQ-057and genome engineering to identify DUBs that are essential for parasite viability or life cycle progression. Burge et al. report on the characterisation of 28 enzymes of the Leishmania ubiquitination pathway and show that many are required for life cycle progression or infection. The proteins UBC2 and UEV1 were studied in more depth because of their importance in the promastigote to amastigote transition. X-ray crystal structure analysis showed these proteins to form a heterodimer with a highly conserved interface. Whereas the UbC2-UEV1 dimer forms K63 linked diubiquitin chains (in vitro), UBC2 can also co-operate in vitro with human E3 enzymes (RNF8 and BIRC2) to form (non-K63-linked) polyubiquitin chains. Overall, ubiquitin enzymes play an important role in Leishmania in vivo infection and they represent potential drug targets in this parasite.

(1) Hameed et al. (2020). Frontiers Chem., Diubiquitin-Based NMR Analysis: Interactions Between Lys6-Linked diUb and UBA Domain of UBXN1
van Kruijsbergen et al. (2020). Frontiers Chem., Strategy for Development of Site-Specific Ubiquitin Antibodies. 
Damianou et al. (2020) Plos Pathogens, Essential roles for deubiquitination in Leishmania life cycle progression.
Burge et al. (2020) Biorxiv., Leishmania differentiation requires ubiquitin conjugation mediated by a UBC2-UEV1 E2 complex.
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