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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Available from: Yihong Ye
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    • "Discovered in the 1980s, primarily for its role in protein degradation, ubiquitin (Ub) is now recognized as a multi-faceted post-translational modifier that regulates protein localization, binding partners, and enzymatic activity, in addition to its well-described role in targeting proteins to the proteasome. In humans, the attachment of Ub to proteins is catalyzed by an enzymatic cascade that first involves the Bactivation^ of Ub by one of two known Ub activating enzymes (E1s) that then transfer Ub to one of approximately 50 Ub-conjugating enzymes (E2s) (Schulman and Harper 2009; Ye and Rape 2009) (Fig. 1a). The final transfer of Ub to a protein target, typically on the ε-amino group of a lysine residue, is facilitated by one of over 500 Ub ligases (E3s) that dock with E2s and dictate substrate specificity (Deshaies and Joazeiro 2009). "
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    • "First, we focused our attention on the E2-conjugase that participates in the ubiquitination reaction. We found that the ubiquitin conjugating enzyme E2-N (UBE2N; Ubc13), one of the more than 38 different E2 conjugating enzymes which are encoded in the human genome (Ye and Rape, 2009), interacts with the malin–laforin complex and modulates its function. Second, we have also found a physical and functional interaction between p62 and the malin–laforin complex, highlighting the relationship between this complex and autophagy. "
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    ABSTRACT: Lafora disease (LD, OMIM254780, ORPHA501) is a rare neurodegenerative form of epilepsy related to mutations in two proteins: laforin, a dual specificity phosphatase, and malin, an E3-ubiquitin ligase. Both proteins form a functional complex, where laforin recruits specific substrates to be ubiquitinated by malin. However, little is known about the mechanism driving malin-laforin mediated ubiquitination of its substrates. In this work we present evidence indicating that the malin-laforin complex interacts physically and functionally with the ubiquitin conjugating enzyme E2-N (UBE2N). This binding determines the topology of the chains that the complex is able to promote in the corresponding substrates (mainly K63-linked polyubiquitin chains). In addition, we demonstrate that the malin-laforin complex interacts with the selective autophagy adaptor sequestosome-1 (p62). Binding of p62 to the malin-laforin complex allows its recognition by LC3, a component of the autophagosomal membrane. In addition, p62 enhances the ubiquitinating activity of the malin-laforin E3-ubiquitin ligase complex. These data enrich our knowledge on the mechanism of action of the malin-laforin complex as an E3-ubiquitin ligase and reinforces the role of this complex in targeting substrates towards the autophagy pathway.
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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.
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