News

For many years, it has thought that eight types of ubiquitin chain can be formed in cells in which the C-terminal carboxylate of ubiquitin forms isopeptide bonds with the ε-amino group of any of the seven lysine residues in another ubiquitin molecule or a peptide bond with the α-amino group of the N-terminal methionine residue of another ubiquitin (Met1-linked ubiquitin). These ubiquitin dimers adopt different conformations and interact with distinct ubiquitin-binding proteins that function to decode the ubiquitin signal.

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Dr. Mahima Swamy from the Medical Research Council Protein Phosphorylation and Ubiquitylation Unit (MRC-PPU) in the University of Dundee has been chosen to join the prestigious EMBO Young Investigator network, recognizing her as one of the rising stars in biology in Europe.

The European Molecular Biology Organization (EMBO) Young Investigator programme (YIP) supports the scientific endeavours of researchers who have become laboratory group leaders in the last 4 years. EMBO Young Investigators are selected by a team of EMBO Members for the high standard of their research and an excellent track record.

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Dr Greg Findlay and Professor Satpal Virdee, Principal Investigators in the MRC Protein Phosphorylation and Ubiquitylation Unit, have been awarded Wellcome Discovery Awards. The 8-year funding that totals ~£4.2M will support their research in Intellectual Disability and E3 ligase enzymes, respectively.

This new scheme from the Wellcome Trust ‘provides funding for established researchers and teams from any discipline who want to pursue bold and creative research ideas to deliver significant shifts in understanding that could improve human life, health and wellbeing’.

Greg Findlay

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Nick Brewer, Ian Ganley, and Yogesh Kulathu have been promoted to Personal Chair (Professor) as part of the 2022 Annual Review process for academic staff.

Nick Brewer

Nick is a member of the D’Arcy Thompson Unit (DTU) and achieved his promotion in recognition of a significant body of work focussed on the student journey (widening access, retention and progression) and student experience for undergraduate students across the School and Wider University.

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On November 7 of this year, the Parkinson’s UK’s leadership team including CEO Caroline Rassell, Deputy director of research Professor David Dexter and the new Scotland director James Jopling visited the Parkinson’s research team at the University of Dundee. In the morning, researchers from Dundee including Professor Dario Alessi, Dr. Paul Davies, Professor Miratul Muqit, Dr. Andy Howden, Professor Ian Ganley and Dr. Esther Sammler, from Aberdeen Professor Bettina Platt and Julie Jones, from St. Andrews Doris Chen and from Edinburgh, Professor Tilo Kunath gave an overview of their work.

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Mitochondria and peroxisomes are key eukaryotic metabolic organelles. They perform essential and related roles including fatty acid metabolism and ROS (Reactive Oxygen Species) scavenging. Their dysfunction has been linked to several devastating disorders including those relating to neurodegeneration and cancer and timely removal of damaged/dysfunctional mitochondria or peroxisomes is thought to be critical in preventing disease. Autophagy, a lysosomal degradation pathway, is a significant pathway mediating turnover of intracellular components and it can specifically target mitochondria (termed mitophagy) and peroxisomes (termed pexophagy).

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Discovered only in 2004, UFM1 is the most recently identified Ubiquitin-like protein. Like ubiquitin, UFM1 is post-translationally attached to proteins via an enzymatic cascade. Ribosomes located at the endoplasmic reticulum, the large molecular machines that carry out protein synthesis, are the main cellular targets of UFM1 attachment. This modification, UFMylation, is crucial for membrane and secretory protein biogenesis and failure in UFMylation has been linked to several developmental and neurological disorders. While UFM1 is important for cellular homeostasis, the mechanisms of how UFM1 is attached onto protein targets have remained enigmatic.

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Targeted protein degradation has become an exciting new drug modality. Tens of small molecule degraders, including proteolysis-targeting chimeras (PROTACs), have entered clinical trials to treat many different diseases.

PROTACs are heterobifunctional molecules that recruit a target protein to an enzyme called E3 ubiquitin ligase, which then marks the target protein for degradation by the cell’s own waste disposal machinery, namely the proteasome. Where a target protein is located within the cell could therefore have an influence on how well the target protein is degraded by PROTACs but this was unknown.

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Mutations that increase the kinase activity of LRRK2 cause Parkinson's disease and therapies that reduce LRRK2 kinase activity are being tested in clinical trials.

Numerous rare variants that alter the amino acid sequence of LRRK2 have been reported that are of unknown clinical significance. Alexia Kalogeropulou, Elena Purltye and Francesca Tonelli with support from Esther Sammler and Shalini Padmanabhan from The Michael J Fox Foundation were keen to establish a workflow to define whether a given variant impacts LRRK2 kinase activity.

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Congratulations to Asad Malik (Phd Student) and Athanasios Karapetsas (ex MRC PPU postdoc, now working in AstraZeneca) for their tremendous work that has elucidated the mechanism of activation of the Leucine-rich-repeat-kinase 1 (LRRK1) protein kinase.

LRRK1 is a close homologue of the LRRK2 protein kinase that is implicated in Parkinson’s disease. Both LRRK1 and LRRK2 are multidomain kinases possessing a ROC-CORA-CORB containing GTPase domain and phosphorylate distinct Rab proteins.

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