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

Eldeeb, Mohamed A.; Leitao, Luana C.A.; Fahlman, Richard P.

doi:10.1139/bcb-2017-0274

Cited by 18 publications

(16 citation statements)

References 73 publications

(60 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In agreement with these results, even a partial ablation of the Arg/N-degron pathway sensitizes cells to apoptosis (55). In sum, the Arg/N-degron pathway is a regulator of apoptosis, acting largely (but not necessarily exclusively) (34) as an antiapoptotic circuit (55). By destroying proapoptotic Ct-fragments, the Arg/N-degron pathway contributes to thresholds that prevent a transient or otherwise weak proapoptotic signal from reaching the point of commitment to apoptosis.…”

Section: Accelerators Of Apoptosis As Arg/n-degron Substratessupporting

confidence: 68%

“…1 and 2 and SI Appendix, Fig. S2A) (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41). Other studies, in the 1990s and afterward, have also identified many internal degrons, defined as degradation signals whose functionally essential elements do not include either Nt-residues or C-terminal (Ct) residues.…”

Section: Terminology For Proteolytic Pathways That Target N-termini Amentioning

confidence: 99%

See 1 more Smart Citation

N-degron and C-degron pathways of protein degradation

Varshavsky

2019

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

431

501

View full text Add to dashboard Cite

This perspective is partly review and partly proposal. N-degrons and C-degrons are degradation signals whose main determinants are, respectively, the N-terminal and C-terminal residues of cellular proteins. Ndegrons and C-degrons include, to varying extents, adjoining sequence motifs, and also internal lysine residues that function as polyubiquitylation sites. Discovered in 1986, N-degrons were the first degradation signals in short-lived proteins. A particularly large set of C-degrons was discovered in 2018. We describe multifunctional proteolytic systems that target N-degrons and C-degrons. We also propose to denote these systems as "N-degron pathways" and "C-degron pathways." The former notation replaces the earlier name "N-end rule pathways." The term "N-end rule" was introduced 33 years ago, when only some N-terminal residues were thought to be destabilizing. However, studies over the last three decades have shown that all 20 amino acids of the genetic code can act, in cognate sequence contexts, as destabilizing N-terminal residues. Advantages of the proposed terms include their brevity and semantic uniformity for N-degrons and C-degrons. In addition to being topologically analogous, N-degrons and C-degrons are related functionally. A proteolytic cleavage of a subunit in a multisubunit complex can create, at the same time, an Ndegron (in a C-terminal fragment) and a spatially adjacent C-degron (in an N-terminal fragment). Consequently, both fragments of a subunit can be selectively destroyed through attacks by the N-degron and C-degron pathways.The lifespans of protein molecules in a cell range from less than a minute to many days. Regulated protein degradation protects cells from misfolded, aggregated, or otherwise abnormal proteins, and also controls the levels of proteins that evolved to be short-lived in vivo. Some proteolytic pathways can selectively destroy a specific subunit of a protein complex. Such pathways can act as proteinremodeling devices (1). They can either activate or inactivate a protein machine, change its enzymatic specificity, alter its subunit composition, or repair an oligomeric complex, for example, by destroying fragments of a cleaved subunit that are still embedded in the complex. This would allow a replacement of the cleaved subunit by its intact counterpart. Many biological transitions involve remodeling of protein complexes through subunit-selective degradation, in settings that range from cell-division cycles and circadian circuits to cell differentiation and responses to stresses.One function of protein degradation is the quality control of nascent and newly formed proteins. Selective proteolysis eliminates those proteins (including mutant ones) that fold too slowly, misfold, or do not satisfy other requirements of quality control. Most proteins function as multisubunit complexes, which often assemble cotranslationally. Quality-control systems destroy subunits that are either overproduced relative to other subunits of a complex or do not become incorporated into a complex rapi...

show abstract

Section: Accelerators Of Apoptosis As Arg/n-degron Substratessupporting

confidence: 68%

Section: Terminology For Proteolytic Pathways That Target N-termini Amentioning

confidence: 99%

N-degron and C-degron pathways of protein degradation

Varshavsky

2019

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

431

501

View full text Add to dashboard Cite

show abstract

“…C, Docking scores of the 20 residues Icl1, Fbp1, and Mdh2 degrons in wild type (red) and (Pro 1 ▶ Ser 1 ) mutated (blue) forms the docking scores (Figure 4), a longer peptide has little influence on the binding affinity. Mdh2 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] . Generally, the docking scores and interaction patterns of the three mutated peptides are comparable.…”

Section: N-end Proline Recognitionmentioning

confidence: 99%

“…Second, the ubiquitin is transferred to the E2 conjugating enzyme . Finally, is the ligation of the polyubiquitin to the destabilized protein through its cognate E3 ligase enzyme ( recognin ) in order to be shredded by the ATP‐dependent 26S proteasome . A mammalian genome encodes more than 800 E3 Ub‐ligases which target different degrons.…”

Section: Introductionmentioning

confidence: 99%

“…3 Finally, is the ligation of the polyubiquitin to the destabilized protein through its cognate E3 ligase enzyme (recognin) in order to be shredded by the ATP-dependent 26S proteasome. [4][5][6][7] A mammalian genome encodes more than 800 E3 Ub-ligases which target different degrons. The diversity of ligases confer the UPS pathways to contribute to almost every physiological process in eukaryotes.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Recognition of gluconeogenic enzymes; Icl1, Fbp1, and Mdh2 by Gid4 ligase: A molecular docking study

Elfiky

Ismail

Elshemey

2019

J of Molecular Recognition

View full text Add to dashboard Cite

The pro/N‐degron pathway is an evolved protein degradation pathway through the ubiquitin‐proteasome system. It is a vital pathway to attain protein homeostasis inside the liver cells with varying glucose levels. N‐terminal proline exists in more than 300 proteins in Saccharomyces cerevisiae, but only three of them are the gluconeogenic enzymes; isocitrate lyase (Icl1), fructose‐1,6‐bisphosphatase (Fbp1), and malate dehydrogenase (Mdh2). The present in silico study aims to structurally illustrate the binding of Icl1 enzyme to Gid4 ligase concerning its peers; Fbp1 and Mdh2. Based on the molecular docking scores and interactions, one can attribute the binding stability of Gid4 with degrons, to peptides of length six up to eight from the N‐terminal. Moreover, the percent change in the docking score provides a rationale for the unique Gid4‐Icl11‐4 interaction. The present study provides insights on the binding attitude of Gid4 ligase to degrons of different lengths, so one will consider in designing peptidomimetics to target Gid4 ligase.

show abstract

Does N‐Terminal Protein Acetylation Lead to Protein Degradation?

et al. 2019

Self Cite

View full text Add to dashboard Cite

The N-end rule denotes the relationship between the identity of the amino-terminal residue of a protein and its in vivo half-life. Since its discovery in 1986, the N-end rule has generally been described by a defined set of rules for determining whether an amino-terminal residue is stabilizing or not. However, recent studies are revealing that this N-end rule (or N-degron concept) is less straightforward than previously appreciated. For instance, it is unveiled that N-terminal acetylation of N-terminal residues may create a degradation signal (Ac-degron) that promotes the degradation of target proteins. A recent high-throughput dissection of degrons in yeast proteins amino termini intriguingly suggested that the hydrophobicity of amino-terminal residues-but not the N-terminal acetylation status-may be the indispensable feature of amino-terminal degrons. Herein, these recent advances in N-terminal acetylation and the complexity of N-terminal degradation signals in the context of the N-degron pathway are analyzed.

show abstract

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

Cited by 18 publications

References 73 publications

N-degron and C-degron pathways of protein degradation

N-degron and C-degron pathways of protein degradation

Recognition of gluconeogenic enzymes; Icl1, Fbp1, and Mdh2 by Gid4 ligase: A molecular docking study

Does N‐Terminal Protein Acetylation Lead to Protein Degradation?

Contact Info

Product

Resources

About