LAUSR

Significance Multicellular organisms synthesize a specific set of proteins in each cell type to enable cellular differentiation and functions. These proteins interact with each other to form complexes needed for various cellular processes. Despite recent advances in cell-specific transcriptomics, very few methods can robustly profile cell-specific proteomes and interactomes in intact organisms without the physical isolation of cells. We developed a chemical biology approach to label proteins from specific cells with a bifunctional amino acid probe that carries both a bio-orthogonal tag for affinity purification and a photo-cross-linker for capturing protein–protein interaction. This method only requires cell-specific expression of an engineered aminoacyl-tRNA synthetase that incorporates the probe into proteins and can be applied to a broad range of organisms.