Scientists unravel mechanisms that stop proteins misbehaving


Protein chains folding and twisting together

Scientists have shed new light on the behaviour of proteins in cells, which could lead to fresh approaches for tackling diseases, including cancer.

Proteins are produced by cells to perform many different tasks, from building new cells to fighting off infections. In order to perform each of these tasks, the proteins must fold themselves into particular shapes.

If the proteins are not folded correctly they are unable to function and they can also damage the cell, which can lead to the onset of degenerative diseases such as Alzheimer’s and Parkinson’s, as well as to some types of cancer.

Because proteins are so important to a cell’s function, it invests a lot of energy into ensuring that folding is done properly and any errors are corrected– but the ways in which it does this have not been well understood.

Scientists at Imperial College London have been investigating the folding mechanisms of a particular class of proteins, called secretory proteins. These include hormones, enzymes and antimicrobial peptides, which are part of the body’s immune system.


The team unravelled the processes through which the cell can detect and take remedial action when proteins are misfolded. This is most likely to happen when the cell suddenly requires a large number of proteins – such as insulin, for example.

The key is in the roles played by two other types of protein within the cell – a chaperone protein, called BiP, and a sensor protein that will activate a signalling system within the cell. This signalling system, called the unfolded protein response, or UPR), tells the cell to take action on misfolded proteins.

Understanding how this complex process works opens up new ways for scientists to think about drug development

– Dr Maruf Ali

The chaperone protein is able to bind itself to the sensor protein to prevent it from becoming active until misfolded proteins are present. Misfolded proteins are detected by BiP, which then detaches itself from the sensor proteins to allow them to trigger the UPR. Once this has happened, BiP binds instead to the problem protein and helps it to fold properly.

 “Understanding how this complex process works opens up new ways for scientists to think about drug development,” says Dr Maruf Ali, of Imperial College London’s Department of Life Sciences.

“A good example could be in cancer treatments. Cancer cells have to exist in harsher environments because they are continually taking nutrients from their surroundings. They have certain survival modes, and one of these is to be able to trigger the unfolded protein response, to ensure protein production continues and the cell can survive. If we can understand more precisely how this system works, we will be better able to interfere with it to stop the progress of the disease.”

The research is funded by Cancer Research UK and the Medical Research Council and published in the journal eLife.

Reference: Carrara, M et al, 2015. Noncanonical binding of BiP ATPase domain to Ire1 and Perk is dissociated by unfolded protein CH1 to initiate ER stress signaling. eLife, 18 February 2015.



Laura Gallagher

Laura Gallagher
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