Scientific accomplishments in 2019 and best wishes for 2020
As we are near the end of this year, we would like to thank our worldwide scientific colleagues for their trust and collaborations. We are proud to be part of various exciting projects, and as such we have outlined below some important published insights which resulted from these collaborations:
An international collaboration led by Prof Daniel Krappmann (Helmholtz Zentrum München) reported in Nature Communications the identification of the DUB Otulin as a regulator of the levels of nutrient transporters on the cell surface. This insight is important for potential treatments of metabolic diseases.
Stangl et al. (2019). Regulation of the endosomal SNX27-retromer by OTULIN.
An international collaboration led by Dr Elton Zeqiraj
(University of Leeds, UK) and Prof Roger Greenberg
(University of Pennsylvania, US) reported in Nature
the cryo-electron microscopy structure of the human BRISC–SHMT2 complex, which is involved in cell metabolism and immune response. The structure showed that (inactive dimeric) SHMT2 inhibits the BRCC36 deubiquitylase activity of BRISC by steric hindrance of the BRCC36 active site. Since pyridoxal-5′-phosphate (PLP, the active form of vitamin B6) stabilizes SHMT2 in an active tetrameric state, the study identified an important mechanism in which a metabolite (PLP) regulates immune signalling by interfering with ubiquitin signalling (i.e. BRISC activity). This insight is important for potential treatments of metabolic and auto-immune diseases. Walden et al. (2019). Metabolic control of BRISC–SHMT2 assembly regulates immune signalling.
A collaboration led by Prof Titia Sixma
(Netherlands Cancer Institute, Netherlands) was reported in Nature Communications
and describes a
detailed mechanistic study of the deubiquitinating enzyme USP7, which is involved in processes such as DNA damage response and apoptosis. Understanding how USP7 achieves specificity for its many cellular targets is important for future clinical development of USP7 inhibitors. Kim et al. (2019). Kinetic analysis of multistep USP7 mechanism shows critical role for target protein in activity.
A collaboration led by Prof Lizbeth Hedstrom
(Brandeis University, US) reported in Bioorganic & Medicinal Chemistry Letters
a series of diarylcarbonates as promiscuous deubiquitinating enzyme (DUB) inhibitor. In contrast to other promiscuous inhibitors, the reported class of diarylcarbonate inhibitors shows a relatively small off-target spectrum and does not induce insoluble ubiquitin aggregates. Overall, the diarylcarbonates serve as valuable research tools for the study of regulatory pathways, stabilizing lysates and as starting points for the design of more selective DUB inhibitors. Long et al. (2019). Diarylcarbonates are a new class of deubiquitinating enzyme inhibitor.
In addition, we are happy to announce that UbiQ
and Prof Titia Sixma
(Netherlands Cancer Institute, Netherlands) were recently awarded a public-private partnership grant by Health-Holland, which is part of the Dutch Life Sciences & Health (LSH) sector. Here, research tools developed by Farid El Oualid and targeted specifically at ubiquitin metalloproteases will be validated and improved with colleagues at the Netherlands Cancer Institute. To date, reagents to study the family of ubiquitin metalloproteases have been almost non-existent and the envisioned research tools hold great potential for the scientific community and can form a basis for future drug development aimed at ubiquitin metalloproteases. https://www.health-holland.com/project/2019/towards-new-drug-therapies-by-a-better-understanding-of-ubiquitin-metalloprotease-activity
Finally, we would like to wish everyone a happy holiday and we look forward to serving and working with the scientific community in the new year.