The N-end rule links the identity of the N-terminal amino acid of a protein to its in vivo half life as some N-terminal residues confer metabolic instability to a protein via their recognition by the cellular machinery that targets them for degradation. Since its discovery, the N-end rule has generally been defined as set of rules of whether an N-terminal residue is stabilizing or not.However, recent studies are revealing that the N-terminal code of amino acids conferring protein instability is more complex than previously appreciated as recent investigations are revealing that the identity of adjoining downstream residues can also influence the metabolic stability of N-end rule substrate. This is exemplified by the recent discovery of a new branch of N-end rule pathways that target proteins bearing N-terminal proline. In addition, recent investigations are demonstrating that the molecular machinery in N-termini dependent protein degradation may also target proteins for lysosomal degradation, in addition to proteasome dependent degradation.Herein, we describe some of the recent advances in N-end rule pathways discuss some of the implications regarding the emerging additional sequence requirements.

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