Regulation of the Gid ubiquitin ligase recognition subunit Gid4

Menssen, Ruth; Bui, Kevin; Wolf, Dieter H.

doi:10.1002/1873-3468.13229

Cited by 29 publications

(39 citation statements)

References 24 publications

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“…First, in carbon recovery conditions that prompt degradation of gluconeogenesis enzymes, Gid1, Gid8, Gid5, Gid4, Gid9 and Gid2 comigrate, suggesting these subunits form a minimal stable E3 ligase including the substrate receptor Gid4, that we term GID SR4 . Second, as expected, the relative level of Gid4 is highest during carbon recovery, in agreement with Gid4 expression being the glucose-regulated switch determining E3 activity (Menssen et al, 2018;Santt et al, 2008). Finally and unexpectedly, during carbon stress, the levels of all GID SR4 subunits except Gid4 increase, and they comigrate in the density gradients.…”

Section: Carbon-source Dependent Anticipatory Versus Activated Gid E3supporting

confidence: 80%

“…Moreover, Fbp1, Mdh2, and Icl1 each harbor natively exposed GID E3-targeting N-terminal prolines essential for their degradation (Hammerle et al, 1998). The question of how their ubiquitylation could be regulated was answered by discovery that glucose availability determines expression of Gid4 (Menssen et al, 2018;Santt et al, 2008), which serves as a substrate receptor for the GID E3 by binding to an N-terminal proline Dong et al, 2018). A crystal structure of peptide-bound human Gid4 showed the basis for Nterminal proline recognition (Dong et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Interconversion between Anticipatory and Active GID E3 Ubiquitin Ligase Conformations via Metabolically Driven Substrate Receptor Assembly

Qiao

Langlois

Chrustowicz

et al. 2019

Preprint

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Qiao et al. (Schulman) -Interconversion between anticipatory and active GID E3 ubiquitin ligase conformations via metabolically-driven substrate receptor assembly 2 SUMMARY Cells respond to environmental changes by toggling metabolic pathways, preparing for homeostasis, and anticipating future stresses. For example, in Saccharomyces cerevisiae, carbon stress-induced gluconeogenesis is terminated upon glucose availability, a process that involves the multiprotein E3 ligase, GID SR4 , recruiting N-termini and catalyzing ubiquitylation of gluconeogenic enzymes. Here, genetics, biochemistry, and cryo electron microscopy define molecular underpinnings of glucose-induced degradation. Unexpectedly, carbon stress induces an inactive anticipatory complex (GID Ant ), which awaits a glucoseinduced substrate receptor to form the active GID SR4 . Meanwhile, other environmental perturbations elicit production of an alternative substrate receptor assembling into a related E3 ligase complex. The intricate structure of GID Ant enables anticipating and ultimately binding various N-degron targeting (i.e. "N-end rule") substrate receptors, while the GID SR4 E3 forms a clamp-like structure juxtaposing substrate lysines with the ubiquitylation active site. The data reveal evolutionarily conserved GID complexes as a family of multisubunit E3 ubiquitin ligases responsive to extracellular stimuli.

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Section: Carbon-source Dependent Anticipatory Versus Activated Gid E3supporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Interconversion between Anticipatory and Active GID E3 Ubiquitin Ligase Conformations via Metabolically Driven Substrate Receptor Assembly

Qiao

Langlois

Chrustowicz

et al. 2019

Preprint

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“…Transition to a medium containing glucose inhibits the synthesis of these enzymes and induces their degradation. As shown by Wolf, Chiang and colleagues, under experimental conditions encompassed in the present study, the degradation of yeast gluconeogenic enzymes is mediated by the multisubunit GID Ub ligase and the 26S proteasome (20,86,87,90,96,97).…”

supporting

confidence: 58%

“…2B Gid4, the main N-recognin of the Pro/N-degron pathway, is a short-lived protein. Gid4 is targeted for degradation largely (though not solely) by the GID Ub ligase, of which Gid4 itself is a subunit (86,97). A GID-recognized degron of Gid4 remains to be identified (Gid4 lacks both Nt-Pro and a Pro at position 2).…”

Section: Resultsmentioning

confidence: 99%

Gid10 as an alternative N-recognin of the Pro/N-degron pathway

Melnykov

Chen

Varshavsky

2019

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

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In eukaryotes, N-degron pathways (formerly “N-end rule pathways”) comprise a set of proteolytic systems whose unifying feature is their ability to recognize proteins containing N-terminal degradation signals called N-degrons, thereby causing degradation of these proteins by the 26S proteasome or autophagy. Gid4, a subunit of the GID ubiquitin ligase in the yeast Saccharomyces cerevisiae, is the recognition component (N-recognin) of the GID-mediated Pro/N-degron pathway. Gid4 targets proteins by recognizing their N-terminal Pro residues or a Pro at position 2, in the presence of distinct adjoining sequence motifs. Under conditions of low or absent glucose, cells make it through gluconeogenesis. When S. cerevisiae grows on a nonfermentable carbon source, its gluconeogenic enzymes Fbp1, Icl1, Mdh2, and Pck1 are expressed and long-lived. Transition to a medium containing glucose inhibits the synthesis of these enzymes and induces their degradation by the Gid4-dependent Pro/N-degron pathway. While studying yeast Gid4, we identified a similar but uncharacterized yeast protein (YGR066C), which we named Gid10. A screen for N-terminal peptide sequences that can bind to Gid10 showed that substrate specificities of Gid10 and Gid4 overlap but are not identical. Gid10 is not expressed under usual (unstressful) growth conditions, but is induced upon starvation or osmotic stresses. Using protein binding analyses and degradation assays with substrates of GID, we show that Gid10 can function as a specific N-recognin of the Pro/N-degron pathway.

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“…A shift to a medium containing glucose inhibits the synthesis of these enzymes and induces their degradation. Degradation of yeast gluconeogenic enzymes requires the multisubunit GID Ub ligase (74,86,87,90,96,97). The ∼600-kDa GID comprises at least the GID1, GID2, GID4, GID5, GID7, GID8, GID9, and GID10 subunits, as well as the weakly associated Ub-conjugating (E2) enzyme UBC8 (GID3) (43,44,46,47,86,96).…”

Section: Significancementioning

confidence: 99%

Recognition of nonproline N-terminal residues by the Pro/N-degron pathway

Cheng

Chen

Melnykov³

et al. 2020

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

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Eukaryotic N-degron pathways are proteolytic systems whose unifying feature is their ability to recognize proteins containing N-terminal (Nt) degradation signals called N-degrons, and to target these proteins for degradation by the 26S proteasome or autophagy. GID4, a subunit of the GID ubiquitin ligase, is the main recognition component of the proline (Pro)/N-degron pathway. GID4 targets proteins through their Nt-Pro residue or a Pro at position 2, in the presence of specific downstream sequence motifs. Here we show that human GID4 can also recognize hydrophobic Nt-residues other than Pro. One example is the sequence Nt-IGLW, bearing Nt-Ile. Nt-IGLW binds to wild-type human GID4 with aKdof 16 μM, whereas the otherwise identical Nt-Pro–bearing sequence PGLW binds to GID4 more tightly, with aKdof 1.9 μM. Despite this difference in affinities of GID4 for Nt-IGLW vs. Nt-PGLW, we found that the GID4-mediated Pro/N-degron pathway of the yeastSaccharomyces cerevisiaecan target an Nt-IGLW–bearing protein for rapid degradation. We solved crystal structures of human GID4 bound to a peptide bearing Nt-Ile or Nt-Val. We also altered specific residues of human GID4 and measured the affinities of resulting mutant GID4s for Nt-IGLW and Nt-PGLW, thereby determining relative contributions of specific GID4 residues to the GID4-mediated recognition of Nt-Pro vs. Nt-residues other than Pro. These and related results advance the understanding of targeting by the Pro/N-degron pathway and greatly expand the substrate recognition range of the GID ubiquitin ligase in both human and yeast cells.

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Regulation of the Gid ubiquitin ligase recognition subunit Gid4

Cited by 29 publications

References 24 publications

Interconversion between Anticipatory and Active GID E3 Ubiquitin Ligase Conformations via Metabolically Driven Substrate Receptor Assembly

Interconversion between Anticipatory and Active GID E3 Ubiquitin Ligase Conformations via Metabolically Driven Substrate Receptor Assembly

Gid10 as an alternative N-recognin of the Pro/N-degron pathway

Recognition of nonproline N-terminal residues by the Pro/N-degron pathway

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