The N-end rule is a fundamental mechanism in protein regulation that links the in vivo half-life of a protein to its N-terminal residue. This rule operates in all organisms, from bacteria to fungi and eukaryotes, and is part of the ubiquitin system. The N-end rule pathway involves the recognition and degradation of proteins bearing specific N-terminal residues, known as degrons. The pathway is initiated by the binding of a targeting complex, typically containing an E3 ligase and a Ub-conjugating enzyme (E2), to the N-terminal residue. The targeting complex then forms a multi-Ub chain, which is recognized by the 26S proteasome for degradation. The N-end rule pathway has several functions, including the elimination of abnormal proteins, maintenance of amino acid pools, and the generation of protein fragments for various cellular processes. It also plays a role in selective destruction of proteins whose concentrations must vary with time and cellular conditions. The pathway is involved in processes such as osmoregulation, peptide import, and apoptosis. The N-end rule pathway is conserved across different organisms, with some differences in the specific enzymes and residues involved. For example, in bacteria like E. coli, the pathway lacks the Ub system but still contains an N-end rule with primary, secondary, and tertiary destabilizing residues. In contrast, eukaryotes have both Ub and the N-end rule pathway, with specific enzymes like N-recognin and N-terminal amidohydrolase (Nta1p) involved in the pathway. The N-end rule pathway has potential applications in various fields, including the control of peptide import, copper homeostasis, and apoptosis. For instance, the pathway may regulate the activity of peptide transporters and influence cellular responses to stress conditions. Additionally, the pathway could be involved in the regulation of apoptosis, where short-lived components of apoptosis modules are degraded by the N-end rule pathway. Overall, the N-end rule pathway is a versatile and evolutionarily conserved mechanism that regulates protein stability and turnover, with implications for various cellular processes and diseases.The N-end rule is a fundamental mechanism in protein regulation that links the in vivo half-life of a protein to its N-terminal residue. This rule operates in all organisms, from bacteria to fungi and eukaryotes, and is part of the ubiquitin system. The N-end rule pathway involves the recognition and degradation of proteins bearing specific N-terminal residues, known as degrons. The pathway is initiated by the binding of a targeting complex, typically containing an E3 ligase and a Ub-conjugating enzyme (E2), to the N-terminal residue. The targeting complex then forms a multi-Ub chain, which is recognized by the 26S proteasome for degradation. The N-end rule pathway has several functions, including the elimination of abnormal proteins, maintenance of amino acid pools, and the generation of protein fragments for various cellular processes. It also plays a role in selective destruction of proteins whose concentrations must vary with time and cellular conditions. The pathway is involved in processes such as osmoregulation, peptide import, and apoptosis. The N-end rule pathway is conserved across different organisms, with some differences in the specific enzymes and residues involved. For example, in bacteria like E. coli, the pathway lacks the Ub system but still contains an N-end rule with primary, secondary, and tertiary destabilizing residues. In contrast, eukaryotes have both Ub and the N-end rule pathway, with specific enzymes like N-recognin and N-terminal amidohydrolase (Nta1p) involved in the pathway. The N-end rule pathway has potential applications in various fields, including the control of peptide import, copper homeostasis, and apoptosis. For instance, the pathway may regulate the activity of peptide transporters and influence cellular responses to stress conditions. Additionally, the pathway could be involved in the regulation of apoptosis, where short-lived components of apoptosis modules are degraded by the N-end rule pathway. Overall, the N-end rule pathway is a versatile and evolutionarily conserved mechanism that regulates protein stability and turnover, with implications for various cellular processes and diseases.