Pharmacological Modulation of the N-End Rule Pathway and Its Therapeutic Implications

Abstract

The N-end rule pathway is a proteolytic system in which single N-terminal amino acids of short-lived substrates determine their metabolic half-lives. Substrates of this pathway have been implicated in the pathogenesis of many diseases, including malignancies, neurodegeneration, and cardiovascular disorders. This review provides a comprehensive overview of current knowledge about the mechanism and functions of the N-end rule pathway. Pharmacological strategies for the modulation of target substrate degradation are also reviewed, with emphasis on their in vivo implications. Given the rapid advances in structural and biochemical understanding of the recognition components (N-recognins) of the N-end rule pathway, small-molecule inhibitors and activating ligands of N-recognins emerge as therapeutic agents with novel mechanisms of action.

The arginylation branch of the N-end rule pathway positively regulates cellular autophagic flux and clearance of proteotoxic proteins

“…5 The N-end rule pathway in mammals has 2 branches, defined by the nature of N-degrons: the acetylation branch (Ac/N-end rule) and the arginylation branch (Arg/N-end rule). 6,7 In the Arg/N-end rule pathway, the primary destabilizing residues are positively charged amino acids (type 1), such as Arg, Lys, and His, and bulky, hydrophobic amino acids (type 2), such as Phe, Trp, Leu, Tyr, and Ile. The destabilizing residues of the Ac/Nend rule pathway are usually created through the cotranslational N-terminal acetylation of nascent proteins that bear either conventional N-terminal Met (from the start codon) or small, uncharged residues, such as Ala, Val, Ser, Thr, and Cys.…”

“…14 Based on this conformational information, several small, biocompatible Arg/N-end rule inhibitors have been developed to target both the UBR box and the N-domain simultaneously. 7 Among these inhibitors, the sympathomimetic amine derivative, para-chloroamphetamine (PCA) is a potent N-end rule inhibitor, which not only blocks degradation of N-end rule reporter substrates in cultured cells, but also effectively delays degradation of its physiological substrates such as RGS4 (regulator of G-protein signaling 4) in mouse brain tissues. 15,16 Because the genetic nullification of key components of the Arg/ N-end rule pathway often results in embryonic lethality, 7 these inhibitors are expected to provide a more feasible way to study the pathophysiological functions of the pathway.…”

N-terminal methionine excision of proteins creates tertiary destabilizing N-degrons of the Arg/N-end rule pathway

“…The Arg/N-end rule pathway performs a broad range of functions in protein quality control, small peptide sensing, chromosome segregation, DNA repair, stress responses, etc. (9,(15)(16)(17)(18)(19)(20)(21).…”

N-Terminal Acetylation-Targeted N-End Rule Proteolytic System: The Ac/N-End Rule Pathway

“…Nonetheless, the discovery of Ac/N-degrons and the Ac/N-end rule pathway is still the beginning of an entirely new and broad research field. Because Ac/N-degrons are present in nearly all proteins and can be conditionally modulated, a detailed understanding of the Ac/N-end rule pathway will set the stage for new therapeutic approaches based on inhibitors or activators of MetAPs, specific Nt-acetylases, and other components of the Ac/N-end rule pathway, including Ac/N-recognins ( Hwang et al, 2010a ; Lee et al, 2015 ; Park et al, 2015 ).…”

“…Out of ∼30 RGS family proteins in humans, Nt-Cys of Rgs4, Rgs5, and Rgs16 are subject to oxidation, Nt-arginylation, and subsequent degradation by the Arg/N-end rule pathway ( Gibbs, 2015 ; Hu et al, 2005 ; Lee et al, 2005 ; 2015 ). The identification of Rgs2 as an Ac/N-end rule substrate suggests that other RGS proteins, including Rgs1, Rgs6, and Rgs7, may also be substrates of either the Ac/N-end rule or Arg/N-end rule pathways depending on their Nt-sequence contexts and Nt-acetylation states ( Park et al, 2015 ).…”