RING-type E3 ligases: Master manipulators of E2 ubiquitin-conjugating enzymes and ubiquitination

Metzger, Meredith B.; Pruneda, Jonathan N.; Klevit, Rachel E.; Weissman, Allan M.

doi:10.1016/j.bbamcr.2013.05.026

Cited by 475 publications

(487 citation statements)

References 170 publications

Supporting

Mentioning

471

Contrasting

Unclassified

Order By: Relevance

“…In contrast, RING E3 ligases act as adaptors to bring the ubiquitin‐loaded E2 together with the substrate and promote ubiquitin transfer without directly participating in the reaction (Berndsen & Wolberger, 2014; Metzger et al , 2014). E2~ubiquitin intermediates exist in multiple conformations in the apo form that cycle between “open” and “closed” states.…”

Section: Introductionmentioning

confidence: 99%

Functional role of TRIM E3 ligase oligomerization and regulation of catalytic activity

et al. 2016

View full text Add to dashboard Cite

TRIM E3 ubiquitin ligases regulate a wide variety of cellular processes and are particularly important during innate immune signalling events. They are characterized by a conserved tripartite motif in their N‐terminal portion which comprises a canonical RING domain, one or two B‐box domains and a coiled‐coil region that mediates ligase dimerization. Self‐association via the coiled‐coil has been suggested to be crucial for catalytic activity of TRIMs; however, the precise molecular mechanism underlying this observation remains elusive. Here, we provide a detailed characterization of the TRIM ligases TRIM25 and TRIM32 and show how their oligomeric state is linked to catalytic activity. The crystal structure of a complex between the TRIM25 RING domain and an ubiquitin‐loaded E2 identifies the structural and mechanistic features that promote a closed E2~Ub conformation to activate the thioester for ubiquitin transfer allowing us to propose a model for the regulation of activity in the full‐length protein. Our data reveal an unexpected diversity in the self‐association mechanism of TRIMs that might be crucial for their biological function.

show abstract

Section: Introductionmentioning

confidence: 99%

Functional role of TRIM E3 ligase oligomerization and regulation of catalytic activity

et al. 2016

View full text Add to dashboard Cite

show abstract

“…The E2 forms a covalent intermediate with ubiquitin, a conserved 76-amino acid protein, whereas the E3 recruits both the E2ϳubiquitin and the protein substrate targeted for ubiquitination (1). Ubiquitin is typically transferred directly from E2 to the protein substrate, although in some cases an E3ϳubiquitin intermediate is established prior to substrate ubiquitination (2,3).…”

mentioning

confidence: 99%

Ubiquitin-conjugating Enzyme Cdc34 and Ubiquitin Ligase Skp1-Cullin-F-box Ligase (SCF) Interact through Multiple Conformations

Sandoval

Hill

Ziemba

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

“…E3s come in several mechanistically distinct classes, but the most abundant are the RING E3s. The RING domain is characterized by a set of Cys and His residues that coordinate a pair of zinc ions; the RING directly contacts the E2-ubiquitin thioester-linked complex and promotes ubiquitin transfer to a substrate (3). Polyubiquitin chains are formed when the C terminus of one donor ubiquitin is conjugated to one of seven lysine residues, or the ␣-amino group, of an acceptor ubiquitin.…”

mentioning

confidence: 99%

A Conserved C-terminal Element in the Yeast Doa10 and Human MARCH6 Ubiquitin Ligases Required for Selective Substrate Degradation

Zattas

Berk

Kreft

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Specific proteins are modified by ubiquitin at the endoplasmic reticulum (ER) and are degraded by the proteasome, a process referred to as ER-associated protein degradation. In Saccharomyces cerevisiae, two principal ER-associated protein degradation ubiquitin ligases (E3s) reside in the ER membrane, Doa10 and Hrd1. The membrane-embedded Doa10 functions in the degradation of substrates in the ER membrane, nuclear envelope, cytoplasm, and nucleoplasm. How most E3 ligases, including Doa10, recognize their protein substrates remains poorly understood. Here we describe a previously unappreciated but highly conserved C-terminal element (CTE) in Doa10; this cytosolically disposed 16-residue motif follows the final transmembrane helix. A conserved CTE asparagine residue is required for ubiquitylation and degradation of a subset of Doa10 substrates. Such selectivity suggests that the Doa10 CTE is involved in substrate discrimination and not general ligase function. Functional conservation of the CTE was investigated in the human ortholog of Doa10, MARCH6 (TEB4), by analyzing MARCH6 autoregulation of its own degradation. Mutation of the conserved Asn residue (N890A) in the MARCH6 CTE stabilized the normally short lived enzyme to the same degree as a catalytically inactivating mutation (C9A). We also report the localization of endogenous MARCH6 to the ER using epitope tagging of the genomic MARCH6 locus by clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated genome editing. These localization and CTE analyses support the inference that MARCH6 and Doa10 are functionally similar. Moreover, our results with the yeast enzyme suggest that the CTE is involved in the recognition and/or ubiquitylation of specific protein substrates.Selective protein degradation in eukaryotic cells is largely carried out by the ubiquitin-proteasome system. Proteins identified for degradation by the ubiquitin-proteasome system are covalently modified with ubiquitin, a highly conserved 76-residue protein (1, 2). In most cases, ubiquitin is conjugated to the target protein via an amide linkage between its C-terminal glycine and ⑀-amino groups on substrate lysine residues. Ubiquitylation requires an enzyme cascade beginning with an E1 ubiquitin-activating enzyme, which adenylates the ubiquitin C-terminal carboxyl group and subsequently forms a high energy thioester bond with it. Ubiquitin is then transferred from the E1 active site cysteine to a cysteine in an E2 ubiquitinconjugating enzyme. Finally, an E3 ubiquitin ligase mediates ubiquitin transfer from the E2 to the target protein. E3s come in several mechanistically distinct classes, but the most abundant are the RING E3s. The RING domain is characterized by a set of Cys and His residues that coordinate a pair of zinc ions; the RING directly contacts the E2-ubiquitin thioester-linked complex and promotes ubiquitin transfer to a substrate (3). Polyubiquitin chains are formed when the C terminus of one donor ubiquitin is conjugated to one of seven lysine residues, or the ...

show abstract

RING-type E3 ligases: Master manipulators of E2 ubiquitin-conjugating enzymes and ubiquitination

Cited by 475 publications

References 170 publications

Functional role of TRIM E3 ligase oligomerization and regulation of catalytic activity

Functional role of TRIM E3 ligase oligomerization and regulation of catalytic activity

Ubiquitin-conjugating Enzyme Cdc34 and Ubiquitin Ligase Skp1-Cullin-F-box Ligase (SCF) Interact through Multiple Conformations

A Conserved C-terminal Element in the Yeast Doa10 and Human MARCH6 Ubiquitin Ligases Required for Selective Substrate Degradation

Contact Info

Product

Resources

About