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Genetically Encoding Bioorthogonal Functional Groups for Site-selective Protein Labeling

Wei Wan, Yane-Shih Wang and Wenshe R. Liu

Site-selective protein labeling is an indispensible approach in the currently intense chemical biology research area. Studies involving site-selective protein labeling span from the protein dynamic analysis in vitro to the proteinprotein interaction investigation in living cells. In the past decade, multiple methods have been introduced to achieve site-selective protein labeling. These include genetic fusion of green fluorescent protein and its derivatives, selective chemical labeling of proteins with fusion tags, and site-specific modification of noncanonical amino acids that are genetically encoded. Using evolved orthogonal aminoacyl-tRNA synthetase-nonsense suppressor tRNA pairs, noncanonical amino acids with bioorthogonal functional groups such as azide, alkyne, tetrazine, alkene, keto, phenylhalide, etc. have been genetically incorporated into proteins in E. coli, yeast, and mammalian cells. Genetic encoding of these noncanonical amino acids enables multiple ways for site-selective protein labeling both in vitro and in vivo, allowing diverse strategies to interrogate protein functions. This review intends to provide a brief introduction to the genetic noncanonical amino acid incorporation technique and recent progresses in applying this technique to achieve site-selective protein labeling.