A chemical biology route to site-specific authentic protein modifications

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Science  29 Sep 2016:
DOI: 10.1126/science.aah4428

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Many essential biological processes are controlled by post-translational protein modifications. The inability to synthetically attain the diversity enabled by these modifications limits functional studies of many proteins. We designed a three-step approach for installing authentic post-translational modifications into recombinant proteins. We first used the established O-phosphoserine (Sep) orthogonal translation system to create a Sep-containing recombinant protein. The Sep residue is then dephosphorylated to dehydroalanine (Dha). Finally, Zn-Cu promoted conjugate addition to Dha of alkyl iodides enables chemo-selective carbon-carbon bond formation. To validate our approach we produced histone H3, ubiquitin and GFP variants with site-specific modifications, including different methylations of H3K79. The methylated histones stimulate transcription via histone acetylation. This approach offers a powerful tool to engineer diverse designer proteins.

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