Forcing proteins to interact together reveals regulatory circuits within cells.

Francis Crick Institute scientists have devised a new method to identify which protein-protein interactions regulate the growth of cells. Contrary to what they expected, they found that forcing the proteins inside our cells into new and different interactions with each other rarely affects the ability of cells to grow.

Nevertheless, there are a number of diseases caused by proteins being in the wrong place within cells or interacting with the wrong partners. The new 'forced association' technology used in this study will allow researchers to examine such interactions and to search for drugs that will possibly correct the problem.

Dr Peter Thorpe of the Crick (currently based at Mill Hill Laboratory) said: "Our actions often depend on who we interact with: parents, teachers, friends, colleagues. 

"So it is for proteins in the cell: their function depends on which other proteins they work with. If a protein interacts with new partners or moves to a new neighborhood of the cell, it can perform an entirely unexpected function, rewiring the way that a cell works." 

Previous work has shown the remarkable effects of fusing two proteins together that normally are separate, which often makes the proteins behave in a new way. 

This led the Crick team to investigate how cells behave when their proteins are forced into new associations. They developed a method in budding yeast to associate a specific protein with every other protein in the cell, one by one, and to see how these affected cell growth. 

They associated every protein with other proteins from each of the major parts of the cell - such as the nucleus, cell membrane or mitochondria. They then examined whether these new associations and relocations caused problems, slowing the cells' growth or killing them. 

Dr Thorpe said: "To our surprise, most forced associations had no detectable effect, indicating that the cell is remarkably tolerant of new protein-protein interactions. This contradicts a common idea that proteins are very fussy about their partner proteins, and will not work properly if they are forced into new interactions. 

"The associations that do cause a growth defect are informative - they are often between proteins that normally work together, indicating that their association is normally carefully controlled during the regular growth of cells. In other cases the associations identify new regulatory mechanisms, suggesting new ways in which cell growth is controlled"

The paper, Synthetic protein interactions reveal a functional map of the cell, is published in eLife.

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