Building Ubiquitin chains: E2 enzymes at work

Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892, USA.
Nature Reviews Molecular Cell Biology (Impact Factor: 37.81). 11/2009; 10(11):755-64. DOI: 10.1038/nrm2780
Source: PubMed


The modification of proteins with ubiquitin chains can change their localization, activity and/or stability. Although ubiquitylation requires the concerted action of ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s) and ubiquitin ligases (E3s), it is the E2s that have recently emerged as key mediators of chain assembly. These enzymes are able to govern the switch from ubiquitin chain initiation to elongation, regulate the processivity of chain formation and establish the topology of assembled chains, thereby determining the consequences of ubiquitylation for the modified proteins.

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    • "All rights reserved. other hand, formation of K63-linked chains promotes DNA repair, endocytosis and vesicular trafficking or ribosomal protein synthesis (Mukhopadhyay and Riezman 2007; Sato et al. 2008; Ye and Rape 2009). "
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    ABSTRACT: The legume-rhizobium symbiosis contributes large quantities of fixed nitrogen to both agricultural and natural ecosystems. This global impact and the selective interaction between rhizobia and legumes culminating in development of functional root nodules have motivated detailed studies of the underlying mechanisms. We conducted a screen for aberrant nodulation phenotypes using the Lotus japonicus LORE1 insertion mutant collection. Here, we describe the identification of amsh1 mutants that only develop small nodule primordia and display stunted shoot growth, and show that the aberrant nodulation phenotype caused by LORE1 insertions in the Amsh1 gene can be separated from the shoot phenotype. In amsh1 mutants, rhizobia initially became entrapped in infection threads with thickened cells walls. Much delayed, some rhizobia were released into plant cells, however no typical symbiosome structures were formed. Furthermore, cytokinin treatment only very weakly induced nodule organogenesis in amsh1 mutants, suggesting that AMSH1 function is required downstream of cytokinin signaling. Biochemical analysis showed that AMSH1 is an active deubiquitinating enzyme and that AMSH1 specifically cleaves K63-linked ubiquitin chains. Post-translational ubiquitination and deubiquitination processes comprising the AMSH1 deubiquitinating enzyme are thus involved in both infection and organogenesis in Lotus japonicus. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    The Plant Journal 06/2015; 83(4). DOI:10.1111/tpj.12922 · 5.97 Impact Factor
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    • "This is the case for UBE2W and UBE2E2, this dimer initiating Ub chain initiation when combined with the E3 ligase BRCA1 and UBE2N-UBE2V1 dimer elongating Ub chains (Christensen et al., 2007). Similarly, UBE2D was proposed to only initiate ubiquitination and other E2 enzymes might be responsible for the development of Ub chains, which is the case for UBE2D-UBE2K ubiquitination activity within the APC complex (Rodrigo-Brenni and Morgan, 2007; Ye and Rape, 2009). E2 combinations represent thus a possibility of control of Ub chain formation by cells, together with posttranslational modifications and binding with other partners. "
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    ABSTRACT: The Ubiquitin Proteasome System (UPS) is a major actor of muscle wasting during various physio-pathological situations. In the past 15 years, increasing amounts of data have depicted a picture, although incomplete, of the mechanisms implicated in myofibrillar protein degradation, from the discovery of muscle-specific E3 ligases to the identification of the signaling pathways involved. The targeting specificity of the UPS relies on the capacity of the system to first recognize and then label the proteins to be degraded with a poly-ubiquitin (Ub) chain. It is fairly assumed that the recognition of the substrate is accomplished by the numerous E3 ligases present in mammalian cells. However, most E3s do not possess any catalytic activity and E2 enzymes may be more than simple Ub-providers for E3s since they are probably important actors in the ubiquitination machinery. Surprisingly, most authors have tried to characterize E3 substrates, but the exact role of E2s in muscle protein degradation is largely unknown. A very limited number of the 35 E2s described in humans have been studied in muscle protein breakdown experiments and the vast majority of studies were only descriptive. We review here the role of E2 enzymes in skeletal muscle and the difficulties linked to their study and provide future directions for the identification of muscle E2s responsible for the ubiquitination of contractile proteins.
    Frontiers in Physiology 03/2015; 6:59. DOI:10.3389/fphys.2015.00059 · 3.53 Impact Factor
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    • "Assembly of K29-Linked PolyUb PolyUb of several linkage types, including K11, K48, and K63, can be assembled in vitro by E2 enzymes (Bremm et al., 2010; Pickart and Raasi, 2005; Ye and Rape, 2009). In addition, HECT-family ligases have been used to catalyze assembly of K6-linked polyUb (Hospenthal et al., 2013). "
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    ABSTRACT: Polyubiquitin chains regulate diverse cellular processes through the ability of ubiquitin to form chains of eight different linkage types. Although detected in yeast and mammals, little is known about K29-linked polyubiquitin. Here we report the generation of K29 chains in vitro using a ubiquitin chain-editing complex consisting of the HECT E3 ligase UBE3C and the deubiquitinase vOTU. We determined the crystal structure of K29-linked diubiquitin, which adopts an extended conformation with the hydrophobic patches on both ubiquitin moieties exposed and available for binding. Indeed, the crystal structure of the NZF1 domain of TRABID in complex with K29 chains reveals a binding mode that involves the hydrophobic patch on only one of the ubiquitin moieties and exploits the flexibility of K29 chains to achieve linkage selective binding. Further, we establish methods to study K29-linked polyubiquitin and find that K29 linkages exist in cells within mixed or branched chains containing other linkages. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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