Nature Cell Biology 6, pp 97 - 105

A large-scale 'proteomic' approach has identified the complete set of protein interactions involved in a key human immune system signalling pathway implicated in a variety of disease states, including many cancers, reports a study in the February issue of Nature Cell Biology. This snapshot of the hundreds of interactions involved provides the most complete and realistic picture to date of how this regulatory system functions, and identifies many potential targets for therapeutic intervention.

Understanding how cells receive signals from neighboring cells, hormones and growth factors is fundamental to understanding how they perform their biological role. Within a cell, this communication is achieved through signalling machinery that consists of multiple large protein complexes, containing tens or hundreds of individual proteins. Thus, to understand these processes it is necessary to examine a huge number of interactions at once.

Now, a group from Cellzome has modified a technique first used to examine yeast protein complexes to study the complete set of interactions for the TNFalpha/NF-kappaB immune pathway. Well-known proteins involved in this pathway are used as molecular guide posts to purify and subsequently identify all the protein complexes with which they interact. This provides a comprehensive physical map of the protein interactions involved, which includes hundreds of proteins, many previously unknown.

In contrast to the piecemeal identification of individual components through molecule-by-molecule approaches, this large-scale approach provides a description of the complete pathway in a single system, which is a more realistic representation of the functioning signalling machine. Application of these approaches will accelerate our understanding of other biological systems and facilitate drug discovery.