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To comprehensively understand the protein interactome, our group has developed a novel XL-MS method to characterize the structures and interactions of various protein complexes in a high-throughput manner. This approach allows us to handle highly complex samples and simultaneously investigate stable and dynamic protein assemblies by capturing their residue-residue connectivities in vivo. In the future, we aim to unveil the full potential of this technique by designing novel cross-linkers, implementing creative approaches for cross-link enrichment, developing a cutting-edge data analysis pipeline, and applying state-of-the-art MS technology. We integrate expertise from synthetic chemistry, analytical chemistry, mass spectrometry and informatics, aiming to reach unprecedented analytical depth, complexity and precision in interactome profiling.