Tracking cell workhorse leads to new protein cluster clue

23 November 2020



Researchers at UQ’s Queensland Brain Institute have found a way to track the formation of protein clusters in live cells.

Proteins are the primary workhorses in a cell, but if they were just randomly spread out, cells wouldn’t function, explains QBI's Professor Frédéric Meunier.

“To have life, you need order – not chaos – in a cell,” he says.

“You need molecules to huddle in specific ways – which have been very difficult to image until recently.”

Proteins often huddle together into ‘nanoclusters’, and it’s believed this plays an important role in normal cell function, as well as disease.

Nanoclusters linked to Alzheimer’s disease

For example, it’s suspected cells can tune their responses to environmental cues — such as the presence of certain drugs or messages sent by other cells — by increasing or decreasing the amount of certain nanoclusters.

Nanoclusters are also known to contribute to neurodegenerative diseases, such as Alzheimer’s, says Professor Meunier.

“For example, 99 per cent of neurodegeneration involves protein aggregates, which are essentially protein nanoclusters that have gone rogue.”

“Understanding how this happens could be of tremendous value in understanding and treating such diseases.”

Unfortunately, it’s not clear why or how these nanoclusters form, says Professor Meunier.

It would be great to see how proteins interact when they come together to form an active nanocluster, as this would shed light on the nanoclustering behaviour of important proteins.

Nanobodies help track protein

Rachel Gormal, the first author of the study, explains that the major challenge is that nanoclusters can form and disperse very quickly, which means they have been difficult to catch in action.

“None of the current super-resolution microscopy techniques can reliably image the changes in protein conformations, during nanoclustering in live cells,” she says.

She and Professor Meunier wondered if small antibodies, called nanobodies, could help.

Nanobodies bind to a small section of a protein of interest. Importantly, a fluorescent tag can be attached to these nanobodies, making them easy to track in living cells.

Together with their colleagues, Ms Gormal and Professor Meunier designed fluorescent nanobodies to bind to proteins called β2-adrenoceptors, a key part of the body’s response to adrenaline.  It was suspected that β2-adrenoceptors form nanoclusters, but no one had witnessed their formation in a live cells before.

With the help of the fluorescent nanobodies, they discovered that β2-adrenoceptors are indeed very dynamic and form transient nanoclusters.

Tracking protein clusters can benefit medicine

“We discovered that they huddle more in the presence of isoprenaline, which is an analogue of adrenaline,” says Professor Meunier. In addition, depending on the receptors conformation, it responds differently to activation.

“This technique is broadly applicable to other proteins and will help unravel essential dynamics and organization of nanoclusters,” says Ms Gormal.

The next goal is to identify subtle structural changes that enable such nanoclusters to form.

The ability to track nanoclusters and understand their triggers has important implications for medicine, says Professor Meunier.

“For instance, when you want to know if a drug causes too much clustering or, by contrast, not enough.”

This provides an opportunity to study the formation of harmful protein nanoclusters in neurodegenerative diseases. 

“There is now an opportunity to see that clustering begin, and to then design drugs that can prevent it,” says Professor Meunier.

The findings have been published in The Proceedings of the National Academy of Sciences.