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Science
2016 Nov 04;3546312:623-626. doi: 10.1126/science.aah4428.
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A chemical biology route to site-specific authentic protein modifications.
Yang A
,
Ha S
,
Ahn J
,
Kim R
,
Kim S
,
Lee Y
,
Kim J
,
Söll D
,
Lee HY
,
Park HS
.
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Many essential biological processes are controlled by posttranslational 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 posttranslational modifications in recombinant proteins. We first use the established O-phosphoserine (Sep) orthogonal translation system to create a Sep-containing recombinant protein. The Sep residue is then dephosphorylated to dehydroalanine (Dha). Last, conjugate addition of alkyl iodides to Dha, promoted by zinc and copper, enables chemoselective carbon-carbon bond formation. To validate our approach, we produced histone H3, ubiquitin, and green fluorescent protein variants with site-specific modifications, including different methylations of H3K79. The methylated histones stimulate transcription through histone acetylation. This approach offers a powerful tool to engineer diverse designer proteins.
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