Structural insights into the catalysis and regulation of E3 ubiquitin ligases

Buetow, Lori; Huang, Danny T.

doi:10.1038/nrm.2016.91

Cited by 500 publications

(455 citation statements)

References 161 publications

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“…E3 ligases are the key determinants of the ubiquitination process and confer specificity as they select the target protein and in some cases also the type of ubiquitin modification [12–14]. This process is reversible and ubiquitin can be removed from a target by deubiquitinating enzymes (DUBs) [15,16].…”

Section: Introductionmentioning

confidence: 99%

Linear ubiquitin chains: enzymes, mechanisms and biology

Rittinger

Ikeda

2017

Open Biol.

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Ubiquitination is a versatile post-translational modification that regulates a multitude of cellular processes. Its versatility is based on the ability of ubiquitin to form multiple types of polyubiquitin chains, which are recognized by specific ubiquitin receptors to induce the required cellular response. Linear ubiquitin chains are linked through Met 1 and have been established as important players of inflammatory signalling and apoptotic cell death. These chains are generated by a ubiquitin E3 ligase complex called the linear ubiquitin chain assembly complex (LUBAC) that is thus far the only E3 ligase capable of forming linear ubiquitin chains. The complex consists of three subunits, HOIP, HOIL-1L and SHARPIN, each of which have specific roles in the observed biological functions of LUBAC. Furthermore, LUBAC has been found to be associated with OTULIN and CYLD, deubiquitinases that disassemble linear chains and counterbalance the E3 ligase activity of LUBAC. Gene mutations in HOIP, HOIL-1L and OTULIN are found in human patients who suffer from autoimmune diseases, and HOIL-1L mutations are also found in myopathy patients. In this paper, we discuss the mechanisms of linear ubiquitin chain generation and disassembly by their respective enzymes and review our current understanding of their biological functions and association with human diseases.

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Section: Introductionmentioning

confidence: 99%

Linear ubiquitin chains: enzymes, mechanisms and biology

Rittinger

Ikeda

2017

Open Biol.

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“…HECT domain ubiquitin transferases (E3 ligases) catalyze the Lys ubiquitination of numerous cellular proteins and are critical for protein homeostasis and cell signaling (Buetow and Huang, 2016; Scheffner and Kumar, 2014). Like all E3 ligases, HECT enzymes are activated by the participation of upstream E1 and E2 enzymes.…”

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confidence: 99%

A Tunable Brake for HECT Ubiquitin Ligases

et al. 2017

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The HECT E3 ligases ubiquitinate numerous transcription factors and signaling molecules and their activity must be tightly controlled to prevent cancer, immune disorders, and other diseases. In this study we have found unexpectedly that peptide linkers tethering WW domains in several HECT family members are key regulatory elements of their catalytic activities. Biochemical, structural, and cellular analysis has revealed that the linkers can lock the HECT domain in an inactive conformation and block the proposed allosteric ubiquitin binding site. Such linker-mediated autoinhibition of the HECT domain can be relieved by linker post-translational modifications, but complete removal of the brake can induce hyperactive autoubiquitination and E3 self-destruction. These results clarify the mechanisms of several HECT protein cancer associated mutations and provide a new framework for understanding how HECT ubiquitin ligases must be finely tuned to ensure normal cellular behavior.

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“…The identification of ubiquitylated proteins destined for degradation by the proteasome can be difficult without the use of proteasome inhibitors, and these may produce other confounding biological effects [62]. A complicating factor in E3 ligase substrate identification may be the relative insensitivity of many methods to post-translational modifications of ubiquitin, E3 ligases or substrates — which have the potential to alter activity and substrate binding [63,64]. …”

Section: E3 Ligase Substrate Identificationmentioning

confidence: 99%

Systematic approaches to identify E3 ligase substrates

Iconomou

Saunders

2016

Biochemical Journal

153

148

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Protein ubiquitylation is a widespread post-translational modification, regulating cellular signalling with many outcomes, such as protein degradation, endocytosis, cell cycle progression, DNA repair and transcription. E3 ligases are a critical component of the ubiquitin proteasome system (UPS), determining the substrate specificity of the cascade by the covalent attachment of ubiquitin to substrate proteins. Currently, there are over 600 putative E3 ligases, but many are poorly characterized, particularly with respect to individual protein substrates. Here, we highlight systematic approaches to identify and validate UPS targets and discuss how they are underpinning rapid advances in our understanding of the biochemistry and biology of the UPS. The integration of novel tools, model systems and methods for target identification is driving significant interest in drug development, targeting various aspects of UPS function and advancing the understanding of a diverse range of disease processes.

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Structural insights into the catalysis and regulation of E3 ubiquitin ligases

Cited by 500 publications

References 161 publications

Linear ubiquitin chains: enzymes, mechanisms and biology

Linear ubiquitin chains: enzymes, mechanisms and biology

A Tunable Brake for HECT Ubiquitin Ligases

Systematic approaches to identify E3 ligase substrates

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