Figure 1.

Mammalian N-end rule pathway. (A) Arginylation branch of the N-end rule pathway (Arg/N-end rule pathway) in mammals. The tertiary destabilizing Cys residues are oxidized by O₂ or nitric oxide (NO) into the secondary destabilizing residues Cys sulfinate (Cys-SO₂⁻) or Cys sulfonate (Cys-SO₃⁻). N-terminal Asn and Gln are deamidated into Asp and Glu by NTAN1 and NTAQ1, respectively. All of the secondary destabilizing residues expose negatively charged side chains (pink background). Secondary destabilizing residues, such as oxidized Cys, Asp, and Glu, are substrates of arginylation by ATE1 R-transferases. The positively charged side chains of N-terminal Arg, Lys, and His in type 1 destabilizing residues are shown in green. Type 2 destabilizing residues are hydrophobic residues such as Phe, Trp, Tyr, Leu, and Ile. These destabilizing residues are recognized and polyubiquitinated by Arg/N-recognins. In the Arg/N-end rule pathway, Ub can be activated and transferred by UBA1-UBE2A/2B (canonical) or UBA6-USE1 (noncanonical) cognates as E1–E2 systems. (B) Acetylation branch of the N-end rule pathway (Ac/N-end rule pathway) in mammals. N-terminal acetylation occurs at the newly exposed N-terminal residues, such as Ala, Ser, Thr, Val, and Cys, after the N-terminal Met excision by Met-endopeptidases (MetAPs) or at the retained N-terminal Met residue. These residues are recognized by the mammalian Ac/N-recognin TEB4.