A research group led by Professor Xiang David LI of the Chemistry Research Division and Department of Chemistry at the University of Hong Kong has developed a new chemical tool to elucidate protein interaction networks in cells. This tool not only facilitates the identification of the interaction partners of a protein in the complex cellular context, but also simultaneously allows the “visualization” of these protein-protein interactions. The results were recently published in the scientific journal Molecular cell.
In the human body, proteins interact with each other to cooperatively regulate essentially all biological processes ranging from gene expression and signal transduction to the immune response. As a result, deregulated protein interactions often lead to human diseases, such as cancer and Alzheimer’s disease. In modern biology, it is important to comprehensively understand protein interaction networks, which has implications in the diagnosis of disease and may facilitate the development of treatments.
To dissect complex protein networks, one must answer two questions: the “who” and the “how” of protein binding. The “who” refers to the identification of a protein’s interacting partners, while the “how” refers to the specific “binding regions” that mediate these interactions. Answering these questions is difficult, as protein interactions are often too unstable and too transient to be detected. To tackle this problem, Prof. Li’s group previously developed a series of tools to “trap” protein-protein interactions with chemical bonding. This is possible because these tools are equipped with a special light-activated “camera” – a group of diazirine that captures each binding partner of a protein when exposed to UV light. The interactions can then be examined and interpreted. Unfortunately, the “resolution” of this “camera” was relatively low, which means that key information about how proteins interact with each other has been lost. To this end, Prof. Li’s group has now designed a new tool (called ADdis-Cys) which has an improved “camera” to improve “resolution”. An alkyne handle installed next to the diazirine allows you to “zoom in” to clearly see the protein binding regions. Coupled with advanced mass spectrometry, ADdis-Cys is the first tool capable of simultaneously identifying the interacting partners of a protein and locating their binding regions.
In the published article, Prof. Li’s lab was able to comprehensively identify numerous protein interactions – some known and others recently discovered – that are important for the regulation of essential cellular processes such as DNA replication, gene transcription and repair of DNA damage. More importantly, Prof. Li’s lab was able to use ADdis-Cys to reveal the binding regions mediating these protein interactions. This tool could lead to the development of chemical modulators that regulate protein interactions for the treatment of human diseases. As a research tool, ADdis-Cys will find wide-ranging applications in many fields of study, in particular in the diagnosis and therapy of diseases.
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