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The Ratcliffe group investigate the relationship between ADO-catalysed oxidation and NatA-catalysed acetylation of a broad range of protein sequences with N-terminal cysteines. This relationship has implications for O2-dependent protein stability and the hypoxic response.

Members of the Ratcliffe research group, led by Karen Heathcote, have investigated the impact of the oxygen sensitive 2-aminoethanethiol dioxygenase (ADO)-catalysed oxidation on protein sequences with N-terminal cysteines. At the same time, they looked at the acetylation of these same protein sequences catalysed by N-terminal acetyltransferases, in particular NatA, and determined a selectivity for N-terminal cysteines with acidic or polar residues immediately adjacent. This distinction in preference to that of the ADO-catalysed oxidation (which selectively oxidises N-terminal cysteines with adjacent basic or aromatic residues) suggests that ADO and NatA have evolved to modify distinct pools of N-terminal cysteine initiating proteins.

By testing this theory in vitro and in cellulo, the substrate selectivity can be observed, with NatA showing low activity towards all ‘good’ ADO substrate peptides, and vice versa, ADO showing low activity for some of the best NatA substrates, but moderate activity towards other good NatA substrates, indicating a certain flexibility in the selectivity. These results have implications on the stability of O2-dependent proteins and the hypoxic response.

To find out more, read the full paper in Nature Communications.

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