The N-end rule pathway is a proteolytic system in which N-terminal residues of short-lived proteins are recognized by recognition components (N-recognins) as essential components of degrons, called N-degrons. Known N-recognins in eukaryotes mediate protein ubiquitylation and selective proteolysis by the 26S proteasome. Substrates of N-recognins can be generated when normally embedded destabilizing residues are exposed at the N terminus by proteolytic cleavage. N-degrons can also be generated through modifications of posttranslationally exposed pro-N-degrons of otherwise stable proteins; such modifications include oxidation, arginylation, leucylation, phenylalanylation, and acetylation. Although there are variations in components, degrons, and hierarchical structures, the proteolytic systems based on generation and recognition of N-degrons have been observed in all eukaryotes and prokaryotes examined thus far. The N-end rule pathway regulates homeostasis of various physiological processes, in part, through interaction with small molecules. Here, we review the biochemical mechanisms, structures, physiological functions, and small-molecule-mediated regulation of the N-end rule pathway.
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.
The N-end rule pathway is a proteolytic system in which recognition components (N-recognins) recognize a set of N-terminal residues as part of degradation signals (N-degrons). Two studies in this issue report the structures of Ubr boxes, a substrate recognition domain of eukaryotic N-recognins. We discuss how eukaryotic and prokaryotic N-recognins use a similar molecular principle to recognize a different set of N-degrons.
Summary
Intracellular signaling is often mediated by a family of functionally overlapping signal mediators that contain multiple sites interacting with other proteins or ligands with weak affinity (Kd > μM). Conjugation of multiple low-affinity ligands into a high-affinity multivalent molecule provides a means to control the entire protein family within a single intracellular pathway. The N-end rule pathway is a ubiquitin (Ub)-dependent proteolytic system where at least four Ub ligases, called N-recognins, have a common domain critical for binding to type-1 (basic) and type-2 (bulky hydrophobic) destabilizing N-terminal residues of substrates as degrons. The recent development of a heterodivalent inhibitor targeting type-1 and type-2 substrate binding sites of the N-recognin family provides new opportunities to manipulate this proteolytic pathway in biochemical and pathophysiological conditions. We overview the N-end rule pathway as an intracellular target for heterodivalent molecules and discuss the basis of thermodynamics and kinetics related to heterodivalent interactions.
Recent focus on autophagy research has led to new insights on the involvement of ubiquitin (Ub)-mediated signaling as a selectivity factor in autophagy, which is generally considered a nonselective global degradation system. Emerging reports have demonstrated active crosstalk between the Ub-dependent proteolytic system and autophagy. This article highlights recent reports describing Ub-mediated selective autophagy regulated by the Toll-like receptor 4-induced immune response.
In this study, the undoped MnO 2 was deposited using spray pyrolysis technique. The manganese (II) acetate tetra hydrate was taken as 0.1M. The film was then annealed at 450°C for 5 h to obtain crystalline peak. The XRD result for the undoped MnO 2 film shows (110) plane peak with maximum intensity. Optical property shows an increase in transmittance for annealed film and band gap was found to be 2.4 eV. The Electrical property indicates the semiconducting nature of the film. The ZnMn 2 O 4 film was obtained from aqueous solution manganese (II) acetate tetra hydrate and Zinc acetate dihydrate salt of 0.01:0.01 molar concentration. After annealing the film at 450°C for 5 h, the crystalline peak was observed. The XRD results of ZnMn 2 O 4 film shows crystalline peaks of (211) and (111) plane. The optical properties shows an increase in transmittance than MnO 2 film. The structural, electrical and morphology properties of the film as a function of annealing temperature were analysed and reported.
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