Optogenetics with Atomic Precision─A Comprehensive Review of Optical Control of Protein Function through Genetic Code...

Conditional control of protein activity is important in order to elucidate the particular functions and interactions of proteins, their regulators, and their substrates, as well as their impact on the behavior of a cell or organism. Optical control provides a perhaps optimal means of introducing spatiotemporal control over protein function as it allows for tunable, rapid, and noninvasive activation of protein activity in its native environment. One method of introducing optical control over protein activity is through the introduction of photocaged and photoswitchable noncanonical amino acids (ncAAs) through genetic code expansion in cells and animals. Genetic incorporation of photoactive ncAAs at key residues in a protein provides a tool for optical activation, or sometimes deactivation, of protein activity. Importantly, the incorporation site can typically be rationally selected based on structural, mechanistic, or computational information. In this review, we comprehensively summarize the applications of photocaged lysine, tyrosine, cysteine, serine, histidine, glutamate, and aspartate derivatives, as well as photoswitchable phenylalanine analogues. The extensive and diverse list of proteins that have been placed under optical control demonstrates the broad applicability of this methodology.