Control of Protein Quality and Stoichiometries by N-Terminal Acetylation and the N-End Rule Pathway

Smerdel-Ramoya, Anna; Hwang, Cheol-Sang; Varshavsky, Alexander

doi:10.1016/j.molcel.2013.03.018

Cited by 266 publications

(388 citation statements)

References 40 publications

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“…A recent proteomic analysis on NatB, an N-terminal acetylase, has reported that the global protein abundance of NatB substrates is not significantly altered in NatB mutants (Gao et al 2016). This apparent dichotomy may be rationalized in several ways, which include sufficient residual acetylation in the mutant, additional unforeseen sequence specificity of the Ac-N-end rule pathway or that many of the N-termini are inaccessible for the Ac-N-end rule pathway as this pathway has been reported to degrade protein subunits that are in excess of their target complex (Shemorry et al 2013). In support of a model where many of these acetylated N-termini may not be directly accessible for the Ac-N-end rule pathway is the recent report that demonstrates this pathway is involved in the degradation of several HSP90 client proteins (Oh et al 2017).…”

Section: Ac-n-end Rulementioning

confidence: 99%

Emerging branches of the N-end rule pathways are revealing the sequence complexities of N-termini dependent protein degradation

Eldeeb

Leitao

Fahlman

2018

Biochem. Cell Biol.

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The N-end rule links the identity of the N-terminal amino acid of a protein to its in vivo half life as some N-terminal residues confer metabolic instability to a protein via their recognition by the cellular machinery that targets them for degradation. Since its discovery, the N-end rule has generally been defined as set of rules of whether an N-terminal residue is stabilizing or not.However, recent studies are revealing that the N-terminal code of amino acids conferring protein instability is more complex than previously appreciated as recent investigations are revealing that the identity of adjoining downstream residues can also influence the metabolic stability of N-end rule substrate. This is exemplified by the recent discovery of a new branch of N-end rule pathways that target proteins bearing N-terminal proline. In addition, recent investigations are demonstrating that the molecular machinery in N-termini dependent protein degradation may also target proteins for lysosomal degradation, in addition to proteasome dependent degradation.Herein, we describe some of the recent advances in N-end rule pathways discuss some of the implications regarding the emerging additional sequence requirements.

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Section: Ac-n-end Rulementioning

confidence: 99%

Emerging branches of the N-end rule pathways are revealing the sequence complexities of N-termini dependent protein degradation

Eldeeb

Leitao

Fahlman

2018

Biochem. Cell Biol.

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“…Recently Shemorry et al (49) showed that the N-terminally acetylated Cog1 subunit of the multimeric COG complex of S. cerevisiae involved in Golgi transport is a target of the Not4 E3 ligase with subsequent degradation by the proteasome. It could be shown that moderately overexpressed Cog1 could be stabilized by co-expression of interacting subunits of the COG complex.…”

Section: Discussionmentioning

confidence: 99%

Quality Control of a Cytoplasmic Protein Complex

Scazzari¹,

Amm²,

Wolf

2015

Journal of Biological Chemistry

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Background: Superfluous subunits of protein complexes are degraded to avoid unwanted erroneous reactions. Results: A machinery consisting of Hsp70, Cdc48, and components of the ubiquitin-proteasome system eliminates orphan fatty acid synthase subunit Fas2. Conclusion: Chaperone motors and the ubiquitin-proteasome system balance the homeostasis of the fatty acid synthase complex. Significance: Selective proteolysis is a tool to regulate protein complex stoichiometry.

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“…1B) (17,23,24). The degradation signals and E3 Ub ligases of the Ac/N-end rule pathway are called Ac/N-degrons and Ac/N-recognins, respectively.…”

Section: Significancementioning

confidence: 99%

“…1) (9,11,12,(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). The main determinant of an N-degron is a destabilizing N-terminal residue of a protein.…”

mentioning

confidence: 99%

Calpain-generated natural protein fragments as short-lived substrates of the N-end rule pathway

Piatkov

Liu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Calpains are Ca 2+ -dependent intracellular proteases. We show here that calpain-generated natural C-terminal fragments of proteins that include G protein-coupled receptors, transmembrane ion channels, transcriptional regulators, apoptosis controllers, kinases, and phosphatases (Phe-GluN2a, Lys-Ica512, Arg-Ankrd2, Tyr-Grm1, Arg-Atp2b2, Glu-Bak, Arg-Igfbp2, Glu-IκBα, and Arg-cFos), are short-lived substrates of the Arg/N-end rule pathway, which targets destabilizing N-terminal residues. We also found that the identity of a fragment's N-terminal residue can change during evolution, but the residue's destabilizing activity is virtually always retained, suggesting selection pressures that favor a short half-life of the calpain-generated fragment. It is also shown that a self-cleavage of a calpain can result in an N-end rule substrate. Thus, the autoprocessing of calpains can control them by making active calpains short-lived. These and related results indicate that the Arg/N-end rule pathway mediates the remodeling of oligomeric complexes by eliminating protein fragments that are produced in these complexes through cleavages by calpains or other nonprocessive proteases. We suggest that this capability of the Arg/N-end rule pathway underlies a multitude of its previously known but mechanistically unclear functions.proteolysis | calpain substrates | ubiquitin

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Control of Protein Quality and Stoichiometries by N-Terminal Acetylation and the N-End Rule Pathway

Cited by 266 publications

References 40 publications

Emerging branches of the N-end rule pathways are revealing the sequence complexities of N-termini dependent protein degradation

Emerging branches of the N-end rule pathways are revealing the sequence complexities of N-termini dependent protein degradation

Quality Control of a Cytoplasmic Protein Complex

Calpain-generated natural protein fragments as short-lived substrates of the N-end rule pathway

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