Targeted Protein Modification with an Antibody-Based System

The chemical modification of proteins is one of the major mechanisms used to regulate the properties and functions of these macromolecules in the cell. It is therefore of great interest to develop tools to exploit this type of modification for applications in molecular biology, medicine, and biotechnology. Here we present a method of using antibodies to perform post-translational covalent modifications of endogenous proteins in complex environments by exploiting proximity-driven chemistry. The method is based on the ability of antibodies to hold a weakly reactive group close to its intended site of reaction by binding the target protein on a nearby epitope. We characterize this approach by modifying the green fluorescent protein in increasingly complex environments and illustrate its applicability by targeting the disease-associated protein beta-2 microglobulin.