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Impact of the N-terminal amino acid on targeted protein degradation

Abstract The N-terminus of any protein may be used as a destabilization signal for targeted protein degradation. In the eukaryotic cytosol, the signal – the so-called N-degron – is recognized for degradation by (i) the N-end rule, a well-described degradation process involving ɛ-ubiquitination; or (ii) N-terminal ubiquitination, a more recently described pathway. Dedicated E3 ubiquitin ligases known as N-recognins then act on the protein. The proteolytic pathways involve ATP-dependent chambered proteases, such as the 26S proteasome in the cytosol, which generate short oligopeptides. The N-terminus of the polypeptide chain is also important for post-proteasome degradation by specific aminopeptidases, which complete peptide cleavage to generate free amino acids. Finally, in each compartment of the eukaryotic cell, N-terminal methionine excision creates a variety of N-termini for mature proteins. It has recently been shown that the N-terminal methionine excision pathway has a major impact early in targeted protein degradation.