ISMB Commentary: An unexpected role for the enzyme Glutamine Synthetase

October 2018

Prof Francesco Gervasio’s group has contributed to the discovery and clarification of an unexpected, yet fundamental, role of the enzyme glutamine synthetase.

Glutamine synthetase (GS) is an enzyme that converts glutamate and ammonia to glutamine.  GS is expressed in endothelial cells, fundamentally regulating vascular development. However, a group of scientists led by Prof Peter Carmeliet at VIB in Belgium together with Prof Francesco L. Gervasio found that it surprisingly shows little glutamine synthetizing activity in these cells. Instead, GS localizes in membranes due to an expected (and so-far, unknown) auto-palmitoylation activity. This moonlighting activity turns out to be fundamental for vessel sprouting. However, it was unclear how it happens and which residues are involved. The state-of-the art models and simulations by Prof. Gervasio’s group were able to solve the mystery, showing how palmitoyl-COA binds to the active site (see figure, left) and reacts with cysteine 209 to form a covalent bond. Site-directed mutagenesis of Cys209 later confirmed the computational prediction and validated the proposed mode of action. This new finding, published by Nature at the beginning of September, has important implications for anti-cancer drug discovery, as it might lead to new drugs blocking the vascular development in solid cancers.


Role of glutamine synthetase in angiogenesis beyond glutamine synthesis
Eelen, G.,…, Gervasio, F.L.,…, Carmeliet, P.
Nature (2018) 561, 63-69

Posted by ubcg49z in Commentaries, News, Publications

ISMB Commentary: Using deep learning and single cell tracking to understand competitive interactions in cell populations

June 2018

Cell competition is a quality-control mechanism through which tissues eliminate unfit cells. Cell competition can result from short-range biochemical inductions or long-range mechanical cues. However, little is known about how cell-scale interactions give rise to population shifts in tissues, due to the lack of experimental and computational tools to efficiently characterize interactions at the single-cell level. Here, we address these challenges by combining long-term automated microscopy with deep-learning image analysis to decipher how single-cell behavior determines tissue makeup during competition. Using our high-throughput analysis pipeline, we show that competitive interactions between MDCK wild-type cells and cells depleted of the polarity protein scribble are governed by differential sensitivity to local density and the cell type of each cell’s neighbors. We find that local density has a dramatic effect on the rate of division and apoptosis under competitive conditions. Strikingly, our analysis reveals that proliferation of the winner cells is up-regulated in neighborhoods mostly populated by loser cells. These data suggest that tissue-scale population shifts are strongly affected by cellular-scale tissue organization. We present a quantitative mathematical model that demonstrates the effect of neighbor cell–type dependence of apoptosis and division in determining the fitness of competing cell lines.

Dr Alan Lowe

Ref: Local cellular neighbourhood controls proliferation in cell competition
Bove, A., Gradeci, D., Fujita, Y., Banerjee, S., Charras, G., Lowe, A.R.
Mol. Biol. Cell (2017) 28: 3215-3228

This video by the Alan Lowe lab demonstrates the data acquired and software developed as part of the work.


Posted by ubcg49z in Commentaries, Publications

ISMB Research could spell new approach to preventing progression of Huntington’s disease

June 2018

New research from scientists at Birkbeck and UCL points the way to a new approach in preventing progression of Huntington’s disease (HD), by manipulating the mutated protein associated with the disease.

HD is an inherited neurodegenerative disease, thought to affect about 7000 people in the UK. There is currently no treatment or cure for the disease, which causes progressive movement disorders and early death.

The disease is caused by a single mutation, which occurs in a gene that encodes the information to make a protein called huntingtin. The mutation causes this protein to form clumps and this process is associated with the damage to brain cells seen in HD. These clumps – or ‘aggregates’ – have been found in the brains of individuals with HD, but it is not clear how they form.

Using a fluorescent tag to track the mutated protein, the researchers found that it can first form a liquid-like cluster that subsequently converts into the harmful aggregates, which are solid and fibrous. Crucially, the researchers showed, both in isolation and in cells, that the aggregates can be easily dissolved when exposed to a chemical called hexanediol when it is in its early liquid-like form – but the chemical does not have any effect once the clusters have ‘solidified’ into aggregates.

Professor Helen Saibil, who led the study, said: “Our findings suggest that the harmful aggregates associated with Huntington’s disease emerge from a form which could be reversible. If the protein behaves similarly in brain cells, it might be possible to target the liquid clusters and prevent the protein from forming the aggregates which are associated with developing Huntington’s. This could have major implications for slowing or preventing disease progression in the future.”

The research formed the PhD project of Dr Tom Peskett (who was a student on the ISMB’s Wellcome Trust PhD programme) and is published in Molecular Cell. It was also the subject of an article in the Evening Standard on 29 June 2018.

Posted by ubcg49z in Achievements, Publications