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Structural insights into the catalysis and regulation of E3 ubiquitin ligases
Lori Buetow and Danny T. Huang
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Abstract
Covalent attachment of one or more ubiquitin molecules to protein substrates governs numerous eukaryotic cellular processes including apoptosis, cell division and immune response. Ubiquitylated proteins can be targeted for degradation but ubiquitylation also mediates processes such as protein-protein interactions and cell signalling, depending on the type of ubiquitin conjugation. Ubiquitin ligases (E3s) catalyze the final step of ubiquitin conjugation by transferring ubiquitin from ubiquitin-conjugating enzymes (E2s) to substrates. In humans, over 600 E3s contribute to determining the fates of thousands of substrates; hence E3s are tightly regulated to ensure accurate substrate ubiquitylation. Recent findings illustrate how E3s are self-regulated and how they coordinate with E2s and substrates to meticulously conjugate ubiquitin.
E3s are a large family of enzymes that catalyze the covalent attachment of a small protein modifier, ubiquitin, to a plethora of substrates in eukaryotic cells. Ubiquitylation (also known as ubiquitination) plays a fundamental role in nearly all aspects of eukaryotic cellular processes. By marking substrates with ubiquitin, E3s bestow substrates with new protein-protein interaction platforms that alter substrate activity, localization and/or interactions to elicit distinct biological signals.
Ubiquitylation is achieved by the sequential actions of ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2) and a ubiquitin ligase (E3)1–3 (Figure 1a). E1 uses Mg2+-ATP to form a covalent thioester between its catalytic cysteine and the di-glycine motif at the C-terminus of ubiquitin. E1 then transfers ubiquitin via the di-glycine motif to E2’s catalytic cysteine to form an E2~ubiquitin thioester complex (~ indicates a thioester bond). E3s then bind E2~ubiquitin and substrate to facilitate formation of an isopeptide bond between the C-terminal carboxyl of ubiquitin and the ε-amino group of a substrate lysine sidechain or free N-terminal amino group. Successive rounds of E3-catalyzed reactions can produce substrates with polyubiquitin chains linked via one of ubiquitin’s seven lysine residues (Lys6, Lys11, Lys27, Lys29, Lys33, Lys48 and Lys63) or ubiquitin’s N-terminal methionine4 (Figure 1b). Recognition of different ubiquitylation patterns by effectors harboring a ubiquitin-binding domain (UBD) elicits distinct downstream signals. For example, Lys48-linked polyubiquitin targets substrate to the 26S proteasome for degradation5, 6; Lys63-linked polyubiquitin directs substrate to the endocytic pathway7 and regulates kinase activation in the NFκB pathway8, and monoubiquitin plays a role in DNA repair9, 10 and chromatin remodeling11.
Figure 1
Figure 1
Ubiquitin conjugation system.
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Answer:Covalent attachment of one or more ubiquitin molecules to protein substrates governs numerous eukaryotic cellular processes including apoptosis, cell division and immune response. Ubiquitylated proteins can be targeted for degradation but ubiquitylation also mediates processes such as protein-protein interactions and cell signalling, depending on the type of ubiquitin conjugation. Ubiquitin ligases (E3s) catalyze the final step of ubiquitin conjugation by transferring ubiquitin from ubiquitin-conjugating enzymes (E2s) to substrates. In humans, over 600 E3s contribute to determining the fates of thousands of substrates; hence E3s are tightly regulated to ensure accurate substrate ubiquitylation. Recent findings illustrate how E3s are self-regulated and how they coordinate with E2s and substrates to meticulously conjugate ubiquitin
Answer:Covalent attachment of one or more ubiquitin molecules to protein substrates governs numerous eukaryotic cellular processes including apoptosis, cell division and immune response. Ubiquitylated proteins can be targeted for degradation but ubiquitylation also mediates processes such as protein-protein interactions and cell signalling, depending on the type of ubiquitin conjugation. Ubiquitin ligases (E3s) catalyze the final step of ubiquitin conjugation by transferring ubiquitin from ubiquitin-conjugating enzymes (E2s) to substrates. In humans, over 600 E3s contribute to determining the fates of thousands of substrates; hence E3s are tightly regulated to ensure accurate substrate ubiquitylation. Recent findings illustrate how E3s are self-regulated and how they coordinate with E2s and substrates to meticulously conjugate ubiquitinExplanation:
Answer:Covalent attachment of one or more ubiquitin molecules to protein substrates governs numerous eukaryotic cellular processes including apoptosis, cell division and immune response. Ubiquitylated proteins can be targeted for degradation but ubiquitylation also mediates processes such as protein-protein interactions and cell signalling, depending on the type of ubiquitin conjugation. Ubiquitin ligases (E3s) catalyze the final step of ubiquitin conjugation by transferring ubiquitin from ubiquitin-conjugating enzymes (E2s) to substrates. In humans, over 600 E3s contribute to determining the fates of thousands of substrates; hence E3s are tightly regulated to ensure accurate substrate ubiquitylation. Recent findings illustrate how E3s are self-regulated and how they coordinate with E2s and substrates to meticulously conjugate ubiquitinExplanation:regards
Answer:Covalent attachment of one or more ubiquitin molecules to protein substrates governs numerous eukaryotic cellular processes including apoptosis, cell division and immune response. Ubiquitylated proteins can be targeted for degradation but ubiquitylation also mediates processes such as protein-protein interactions and cell signalling, depending on the type of ubiquitin conjugation. Ubiquitin ligases (E3s) catalyze the final step of ubiquitin conjugation by transferring ubiquitin from ubiquitin-conjugating enzymes (E2s) to substrates. In humans, over 600 E3s contribute to determining the fates of thousands of substrates; hence E3s are tightly regulated to ensure accurate substrate ubiquitylation. Recent findings illustrate how E3s are self-regulated and how they coordinate with E2s and substrates to meticulously conjugate ubiquitinExplanation:regards Girisha