Selective N-terminal acylation of peptides and proteins with a Gly-His tag sequence

Manuel C. Martos-Maldonado, Christian T. Hjuler, Kasper K. Sørensen, Mikkel B. Thygesen, Jakob E. Rasmussen, Klaus Villadsen, Søren R. Midtgaard, Stefan Kol, Sanne Schoffelen () and Knud J. Jensen ()
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Manuel C. Martos-Maldonado: University of Copenhagen
Christian T. Hjuler: University of Copenhagen
Kasper K. Sørensen: University of Copenhagen
Mikkel B. Thygesen: University of Copenhagen
Jakob E. Rasmussen: University of Copenhagen
Klaus Villadsen: University of Copenhagen
Søren R. Midtgaard: University of Copenhagen
Stefan Kol: Technical University of Denmark
Sanne Schoffelen: University of Copenhagen
Knud J. Jensen: University of Copenhagen

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract Methods for site-selective chemistry on proteins are in high demand for the synthesis of chemically modified biopharmaceuticals, as well as for applications in chemical biology, biosensors and more. Inadvertent N-terminal gluconoylation has been reported during expression of proteins with an N-terminal His tag. Here we report the development of this side-reaction into a general method for highly selective N-terminal acylation of proteins to introduce functional groups. We identify an optimized N-terminal sequence, GHHHn− for the reaction with gluconolactone and 4-methoxyphenyl esters as acylating agents, facilitating the introduction of functionalities in a highly selective and efficient manner. Azides, biotin or a fluorophore are introduced at the N-termini of four unrelated proteins by effective and selective acylation with the 4-methoxyphenyl esters. This Gly-Hisn tag adds the unique capability for highly selective N-terminal chemical acylation of expressed proteins. We anticipate that it can find wide application in chemical biology and for biopharmaceuticals.

Date: 2018
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DOI: 10.1038/s41467-018-05695-3

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