Chemical barcode

Mathematical and computational approaches show how cells may impose order on the sequence of protein modifications.
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Image credit: Conor Lawless (CC BY 2.0)

Proteins help our cells perform the chemical reactions necessary for life. Once proteins are made, they can also be modified in different ways. This can simply change their activity, or otherwise make them better suited for their specific jobs within the cell. Biological ‘catalysts’ called enzymes carry out protein modifications by reversibly adding (or removing) chemical groups, such as phosphate groups.

‘Multisite modifications’ occur when a protein has two or more modifications in different areas, which can be added randomly or in a specific sequence. The combination of all the modifications attached to a protein acts like a chemical barcode and confers a specific function to the protein.

Modification networks add levels of complexity above individual proteins. These encompass not only the proteins in a cell or tissue, but also the different enzymes that can modify them, and how they all interact with each other. Although our knowledge of these networks is substantial, basic aspects, such as how the ordering of multisite modification systems emerges, is still not well understood.

Using a simple set of multisite modifications, Ramesh and Krishnan set out to study the potential mechanisms allowing the creation of order in this context. Symmetry is a pervasive theme across the sciences. In biology, symmetry and how it may be broken, is important to understand, for example, how organism develop. Ramesh and Krishnan used the perspective of symmetry in protein networks to uncover the origins of ordering.

First, mathematical models of simple modification networks were created based on their basic descriptions. This system centred on proteins that could have phosphate modifications at two possible sites. The network was ‘symmetric’, meaning that the rate of different sets of chemical reactions was identical, as were the amounts of all the enzymes involved.

Dissecting the simulated network using a variety of mathematical approaches showed that its initial symmetry could break, giving rise to sets of ordered multisite modifications. Breaking symmetry did not require any additional features or factors; the basic chemical ‘ingredients’ of protein modification were all that was needed. The prism of symmetry also revealed other aspects of these multisite modification networks, such as robustness and oscillations.

This study sheds new light on the mechanism behind ordering of protein modifications. In the future, Ramesh and Krishnan hope that this approach can be applied to the study of not just proteins but also a wider range of biochemical networks.