New Tools to Reveal How Proteins Recognize and Interact Found

A team led by Professor X. David Li, Department of Chemistry, University of Hong Kong, has developed a new chemical tool to elucidate the network of intracellular protein interactions. This tool not only facilitates the identification of interacting partners of proteins in a complex cellular environment, but also simultaneously allows the "visualization" of the interactions of these proteins. These findings were recently published in Molecular Cells.

In the human body, proteins interact and cooperate to regulate every biological process from gene expression and signal transduction to immune response. Thus, dysregulation of protein interactions often leads to human diseases, such as cancer and Alzheimer's disease. In modern biology, a comprehensive understanding of protein interaction networks is important, which has implications for disease diagnosis and can facilitate the development of therapies.

To dissect complex protein networks, two questions need to be answered: the protein binds to "who" and "how." Who "refers to the recognition of protein interaction partners, while “how” refers to specific “binding regions” that mediate these interactions. Answering these questions is challenging because protein interactions are often too unstable and too transient to detect. To solve this problem, Professor Li's team previously developed a series of tools to "capture" interactions between proteins through chemical bonds. Possibly, because these tools are equipped with a special light-activated “camera”, the diazinyl group, which can capture each binding partner of the protein when exposed to ultraviolet light. These interactions can then be examined and interpreted. Unfortunately, the “resolution” of this “camera” is relatively low, which means that key information about how proteins interact is lost. To this end, Professor Li's team has now designed a new tool (called ADdis-Cys) that has an upgraded “camera” to improve “resolution”. An alkyne stalk was mounted next to the diazoxide, and the binding region of the protein could be clearly seen “zoomed in”. Combined with state-of-the-art mass spectrometry techniques, ADdis-Cys is the first tool capable of simultaneously identifying protein interaction partners and pinpointing their binding regions.

In the published paper, Professor Li's laboratory was able to comprehensively identify many protein interactions, some known and some newly discovered, that are important for regulating important cellular processes, such as DNA replication, gene transcription, and DNA damage repair. Most importantly, Professor Li's laboratory was able to use ADdis-Cys to reveal the binding regions that mediate the interactions of these proteins. Tools may lead to the development of chemical modulators that modulate protein interactions to treat human diseases. As a research tool, adis-cys will discover far-reaching applications in many research fields, particularly in the diagnosis and treatment of diseases.

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