To label proteins covalently,a trade-off between specificity and potential biocompatibility becomes the major concern.Genetic fusion of a reporter such as a fluorescent protein or an enzyme provides the labeling of the protein of interest(POI)with absolute specificity,while using small tags causes less disruption of the parental proteins structure.Often one must compromise one parameter for the other or use additional components,such as an enzyme,to satisfy both requirements.Here,we report a new reaction that covalently labels proteins by using engineered coiled-coil peptides.[1] Harnessing the concept of “proximity-induced reactivity”,the 21-amino acid peptides CCE/CCK were modified with a nucleophilic cysteine and an α-chloroacetyl group at selected positions.When pairs of coiled coils associated,an irreversible covalent bond spontaneously formed between the peptides.The specificity of the cross-linking reaction was characterized,the probes were improved by making them bivalent,and the system was used to label a protein in vitro and receptors on the surface of mammalian cells.