The immune system's cell-splitters revealed in unprecedented detail

Part of the immune system that drills into invading bacteria and splits them open has been visualised in nanoscopic detail, with surprising results.

Membrane attack complexes (MACs) are structures made of proteins that assemble in the body when an infection is detected. They latch on to the membranes of invading bacteria, such as meningitis, and punch a hole in them.

Eventually, if enough MACs punch a hole in the membrane, the bacteria will split open and die. MACs are of particular interest in cancer research, as some cancer cells are able to evade them.

In the new study, published in the journal Nature Communications, researchers from Imperial College London and Cardiff University visualised the MAC using cryo-electron microscopy. This rapidly-advancing technique has the power to visualise complex protein structures at resolutions below a nanometre – one billionth of a metre.

Fly through the structure of the MAC in the video above as different protein groups are highlighted.

The visualisation revealed a surprise. Instead of being a closed symmetric ring of proteins, as was expected by looking at similar protein structures, the MAC was revealed to have a ‘split-washer’ shape, where the ring was broken resulting in a mismatch of the symmetry.

“At the point where the ring splits and the symmetry is mismatched, the MAC doesn’t completely penetrate the bacteria membrane,” said study co-author Dr Doryen Bubeck from the Department of Life Sciences at Imperial.

“This opens up a whole new set of questions about its function. Is it sensing something about the membrane? Is it signalling other proteins?”

Target practice

A certain concentration of MACs is needed to break open a cell, and the researchers suggest that before that concentration has built up, the MACs already on the membrane may be signalling information. Where the ring structure of the MAC is split, it distorts the bacteria membrane rather than cutting through it, and it is this distortion that may create a signalling pathway.

MACs are not specific, meaning they target any membranes they come into contact with. However, the membranes on our own cells are largely protected from attack by a protein called CD59. Some MACs will still punch holes through our cells’ membranes, but not enough to break them.

Some cancer cells can make lots of CD59 to protect themselves, making the protein a target in some immunotherapies for cancer. Knowing more about how MACs function in response to CD59 could help improve drugs that target this mechanism, and this can now be investigated in more detail. The current study was funded by Cancer Research UK.

The study is one of the first in the UK to use cryo-electron microscopy at the electron Bio-Imaging Centre (eBIC) at Diamond Light Source, the UK’s national synchrotron science facility in Oxfordshire.

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'Structural basis of complement membrane attack complex formation' by Marina Serna, Joanna L. Giles, B. Paul Morgan and Doryen Bubeck is published in Nature Communications.