Formyl-methionine as a degradation signal at the N-termini of bacterial proteins

Piatkov, Konstantin; Vu, Tri T. M.; Hwang, Cheol-Sang; Varshavsky, Alexander

doi:10.15698/mic2015.10.231

Cited by 70 publications

(74 citation statements)

References 131 publications

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“…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%

N-degron and C-degron pathways of protein degradation

Varshavsky

2019

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

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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...

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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.

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“…In contrast to nuclear‐derived proteins, plastid‐encoded proteins initiate with Nt‐fMet, and undergo cotranslational deformylation followed by Nt‐Met excision, which are both essential for normal plastid development (Giglione et al ., ; van Wijk, ). Interestingly Met‐retention on chloroplast proteins has previously been linked to protein instability (Giglione et al ., ), whilst fMet can act as a destabilizing residue in bacteria, and possibly also chloroplasts (Piatkov et al ., ). Cotranslational and posttranslational Nt‐acetylation also occurs on chloroplastic proteins, which appears to enhance protein stability (Bienvenut et al ., ); recently a nuclear‐encoded chloroplast‐targeted NAT that probably catalyses this modification has been identified (Dinh et al ., ).…”

Section: The N‐terminus As a Stability Determinant In Plastidsmentioning

confidence: 99%

From start to finish: amino‐terminal protein modifications as degradation signals in plants

et al. 2016

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Summary The amino‐ (N‐) terminus (Nt) of a protein can undergo a diverse array of co‐ and posttranslational modifications. Many of these create degradation signals (N‐degrons) that mediate protein destruction via the N‐end rule pathway of ubiquitin‐mediated proteolysis. In plants, the N‐end rule pathway has emerged as a major system for regulated control of protein stability. Nt‐arginylation‐dependent degradation regulates multiple growth, development and stress responses, and recently identified functions of Nt‐acetylation can also be linked to effects on the in vivo half‐lives of Nt‐acetylated proteins. There is also increasing evidence that N‐termini could act as important protein stability determinants in plastids. Here we review recent advances in our understanding of the relationship between the nature of protein N‐termini, Nt‐processing events and proteolysis in plants.

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“…1) (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). The main determinant of an N-degron is a destabilizing Nt-residue of a protein.…”

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Control of Hsp90 chaperone and its clients by N-terminal acetylation and the N-end rule pathway

Hyun

Varshavsky

2017

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

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We found that the heat shock protein 90 (Hsp90) chaperone system of the yeast Saccharomyces cerevisiae is greatly impaired in naa10Δ cells, which lack the NatA N α -terminal acetylase (Nt-acetylase) and therefore cannot N-terminally acetylate a majority of normally N-terminally acetylated proteins, including Hsp90 and most of its cochaperones. Chk1, a mitotic checkpoint kinase and a client of Hsp90, was degraded relatively slowly in wild-type cells but was rapidly destroyed in naa10Δ cells by the Arg/N-end rule pathway, which recognized a C terminus-proximal degron of Chk1. Diverse proteins (in addition to Chk1) that are shown here to be targeted for degradation by the Arg/N-end rule pathway in naa10Δ cells include Kar4, Tup1, Gpd1, Ste11, and also, remarkably, the main Hsp90 chaperone (Hsc82) itself. Protection of Chk1 by Hsp90 could be overridden not only by ablation of the NatA Nt-acetylase but also by overexpression of the Arg/N-end rule pathway in wild-type cells. Split ubiquitin-binding assays detected interactions between Hsp90 and Chk1 in wild-type cells but not in naa10Δ cells. These and related results revealed a major role of Nt-acetylation in the Hsp90-mediated protein homeostasis, a strong up-regulation of the Arg/N-end rule pathway in the absence of NatA, and showed that a number of Hsp90 clients are previously unknown substrates of the Arg/N-end rule pathway.roteins called chaperones promote the in vivo protein folding and counteract misfolding, maladaptive protein aggregation, and other perturbations of proteostasis (1-4). Hsp90 is an ATPdependent chaperone system that mediates the conformational maturation and stabilization of many proteins. Referred to as Hsp90 clients, these proteins include kinases, transcriptional regulators, and many other proteins that comprise at least 20% of a cellular proteome. The diversity of Hsp90 clients and the broad range of processes that involve Hsp90 underlie its necessity for cell viability in all eukaryotes (5-11). Cochaperones of the ∼90-kDa Hsp90 comprise, in mammals, ∼30 distinct proteins. They participate in the delivery of clients to Hsp90 and contribute to related processes, including ATP hydrolysis by Hsp90 (12). Because of its ability to modulate protein conformations, the Hsp90 system can either exacerbate or counteract the fitness-reducing effects of mutations in cellular proteins. This property of Hsp90 affects the standing genetic variation and thereby influences the impact of natural selection on rates and directions of evolution (13,14).The N-end rule pathways comprise a set of proteolytic systems whose unifying feature is their ability to recognize proteins containing N-terminal (Nt) degradation signals called N-degrons, thereby causing the degradation of these proteins by the proteasome or autophagy in eukaryotes and by the proteasome-like ClpAP protease in bacteria (Fig. 1) (15-26). The main determinant of an N-degron is a destabilizing Nt-residue of a protein. Many N-degrons become active through their enzymatic Nt-acetylation, Ntformylation...

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Formyl-methionine as a degradation signal at the N-termini of bacterial proteins

Cited by 70 publications

References 131 publications

N-degron and C-degron pathways of protein degradation

N-degron and C-degron pathways of protein degradation

From start to finish: amino‐terminal protein modifications as degradation signals in plants

Control of Hsp90 chaperone and its clients by N-terminal acetylation and the N-end rule pathway

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