The N-end rule pathway: Emerging functions and molecular principles of substrate recognition

Center for Pharmacogenetics and Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Nature Reviews Molecular Cell Biology (Impact Factor: 37.81). 11/2011; 12(11):735-47. DOI: 10.1038/nrm3217
Source: PubMed


The N-end rule defines the protein-destabilizing activity of a given amino-terminal residue and its post-translational modification. Since its discovery 25 years ago, the pathway involved in the N-end rule has been thought to target only a limited set of specific substrates of the ubiquitin-proteasome system. Recent studies have provided insights into the components, substrates, functions and structural basis of substrate recognition. The N-end rule pathway is now emerging as a major cellular proteolytic system, in which the majority of proteins are born with or acquire specific N-terminal degradation determinants through protein-specific or global post-translational modifications.

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    • "The N-end rule explains the correlation between a protein's N-terminal amino acid and its in vivo degradation rate12. It is the first identified constituent of the ubiquitin-proteasome system (UPS)-mediated proteolysis in eukaryotes3. "
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    ABSTRACT: In the arginylation branch of the N-end rule pathway, unacetylated N-terminal destabilizing residues function as essential determinants of protein degradation signals (N-degron). Here, we show that a neurostimulant, para-chloroamphetamine (PCA), specifically inhibits the Arg/N-end rule pathway, delaying the degradation of its artificial and physiological substrates, including regulators of G protein signaling 4 (RGS4), in vitro and in cultured cells. In silico computational analysis indicated that PCA strongly interacts with both UBR box and ClpS box, which bind to type 1 and type 2 N-degrons, respectively. Moreover, intraperitoneal injection of PCA significantly stabilized endogenous RGS4 proteins in the whole mouse brain and, particularly, in the frontal cortex and hippocampus. Consistent with the role of RGS4 in G protein signaling, treatment with PCA impaired the activations of GPCR downstream effectors in N2A cells, phenocopying ATE1-null mutants. In addition, levels of pathological C-terminal fragments of TDP43 bearing N-degrons (Arg208-TDP25) were significantly elevated in the presence of PCA. Thus, our study identifies PCA as a potential tool to understand and modulate various pathological processes regulated by the Arg/N-end rule pathway, including neurodegenerative processes in FTLD-U and ALS.
    Scientific Reports 09/2014; 4:6344. DOI:10.1038/srep06344 · 5.58 Impact Factor
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    • "UBR4 belongs to the UBR box protein family of E3 ubiquitin ligases, or N-recognins, that functions in the N-end rule degradation pathway [27]. The N-end rule pathway selectively ubiquitinates substrate proteins based on the presence of specific destabilizing residues, or N-degrons, in their N-termini [27]. "
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    ABSTRACT: Circadian rhythms of behavior and physiology are driven by the biological clock that operates endogenously but can also be entrained to the light-dark cycle of the environment. In mammals, the master circadian pacemaker is located in the suprachiasmatic nucleus (SCN), which is composed of individual cellular oscillators that are driven by a set of core clock genes interacting in transcriptional/translational feedback loops. Light signals can trigger molecular events in the SCN that ultimately impact on the phase of expression of core clock genes to reset the master pacemaker. While transcriptional regulation has received much attention in the field of circadian biology in the past, other mechanisms including targeted protein degradation likely contribute to the clock timing and entrainment process. In the present study, proteome-wide screens of the murine SCN led to the identification of ubiquitin protein ligase E3 component N-recognin 4 (UBR4), a novel E3 ubiquitin ligase component of the N-end rule pathway, as a time-of-day-dependent and light-inducible protein. The spatial and temporal expression pattern of UBR4 in the SCN was subsequently characterized by immunofluorescence microscopy. UBR4 is expressed across the entire rostrocaudal extent of the SCN in a time-of-day-dependent fashion. UBR4 is localized exclusively to arginine vasopressin (AVP)-expressing neurons of the SCN shell. Upon photic stimulation in the early subjective night, the number of UBR4-expressing cells within the SCN increases. This study is the first to identify a novel E3 ubiquitin ligase component, UBR4, in the murine SCN and to implicate the N-end rule degradation pathway as a potential player in regulating core clock mechanisms and photic entrainment.
    PLoS ONE 08/2014; 9(8):e103103. DOI:10.1371/journal.pone.0103103 · 3.23 Impact Factor
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    • "This pathway is highly conserved in eukaryotes and plays a key role in the regulation of many growth and developmental processes, including apoptosis, cardiovascular development, DNA replication, and response to abiotic stresses (Sriram et al., 2011). There are two characterized branches of the N-end rule pathway: the Ac/N-end rule pathway, which targets proteins with N-terminally acetylated (Ac) residues, and the Arg/N-end rule, which recognizes specific unacetylated Nt residues (Sriram et al., 2011). Eukaryotic proteins are synthesized with methionine (Met) at the N terminus, but new N termini can be generated via the action of endopeptidases or by cotranslational cleavage of Nt-Met by methionine aminopeptidases (MAPs). "
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    ABSTRACT: Nitric oxide (NO) is an important signaling compound in prokaryotes and eukaryotes. In plants, NO regulates critical developmental transitions and stress responses. Here, we identify a mechanism for NO sensing that coordinates responses throughout development based on targeted degradation of plant-specific transcriptional regulators, the group VII ethylene response factors (ERFs). We show that the N-end rule pathway of targeted proteolysis targets these proteins for destruction in the presence of NO, and we establish them as critical regulators of diverse NO-regulated processes, including seed germination, stomatal closure, and hypocotyl elongation. Furthermore, we define the molecular mechanism for NO control of germination and crosstalk with abscisic acid (ABA) signaling through ERF-regulated expression of ABSCISIC ACID INSENSITIVE5 (ABI5). Our work demonstrates how NO sensing is integrated across multiple physiological processes by direct modulation of transcription factor stability and identifies group VII ERFs as central hubs for the perception of gaseous signals in plants.
    Molecular cell 01/2014; 53(3). DOI:10.1016/j.molcel.2013.12.020 · 14.02 Impact Factor
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