Helen Saibil

The killer weapon of the immune system

Researchers in Biological Sciences at Birkbeck, in collaboration with a group at the Peter MacCallum Cancer Centre in Melbourne, have determined the structure of a protein assembly used by the immune system to kill unwanted cells. The immune system uses cytotoxic T lymphocytes and natural killer cells to act as executioners when it detects the presence of virally infected or cancerous cells.  The cytotoxic and killer cells contain small membrane parcels filled with the protein perforin, which can punch holes through cell membranes, along with the toxic granzyme enzymes. When an infected cell is detected, the killer cell latches onto it and ejects some of the membrane parcels with their toxic contents so that the perforin protein punches holes in the target cell membrane, through which the toxic granzymes enter, rapidly causing the target cell to die (Figure 1). The cytotoxic and killer cells are professional assassins that can kill many victims in rapid succession, briefly attaching, ejecting their lethal cargo, and then moving on to the next victim. Perforin is an essential protein for survival, and unfortunate individuals who lack functional perforin usually die of infection or cancer in early childhood. On the other hand, over active killer cells can also cause serious damage, by triggering inflammation and killing healthy cells.

A former postdoctoral researcher, Marina Ivanova (now at Imperial College), determined the perforin structure in the group of Professor Helen Saibil, and the paper has been published in Science Advances. Perforin is made as single protein molecules that are stored inside their membrane compartment until they are needed, but when they are released, they join up into rings of around 22 molecules and undergo a dramatic shape change in order to punch the hole through the target membrane. Two parts of the protein that are at first coiled up in the molecule extend and join up into the ring to punch through the membrane. This shape change is shown in Figure 2, with the part of the protein that makes the big change highlighted in pink.

Figure 3 shows two views of a perforin ring (multicoloured molecules) enclosing a hole in a cell membrane (shown as a pale blue slab). Now that we know the details of the pore structure, it will be possible to think about designing drugs to either enhance or prevent its activity. This could eventually lead to new therapeutics for certain autoimmune diseases and the condition familial hemophagocytic lymphohistiocytosis.

Ivanova, M.E., Lukoyanova, N., Malhotra, S., Topf, M., Trapani, J.A., Voskoboinik, I., Saibil, H.R. (2022) The pore conformation of lymphocyte perforin. Science Advances 8, eabk3147.

Posted by ubcg49z in Commentaries, News, 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