Mechanistically, auto- ubiquitination of Mdm2 facilitates the recruitment of the E2 ubiquitin-conjugating enzyme. Mdm2 that has been conjugated to polyubiquitin chains, but not to single ubiquitins, exhibits substantially enhanced activity to polyubiquitinate p53. Here we show that auto- ubiquitination of Mdm2 is an activating event. ![]() How Mdm2 auto- ubiquitination may influence its substrate ubiquitin ligase activity is undefined. Like most E3 ligases, Mdm2 can also ubiquitinate itself. It targets p53 for proteasomal degradation, restraining the potent activity of p53 and enabling cell survival and proliferation. The RING domain E3 ubiquitin ligase Mdm2 is the master regulator of the tumor suppressor p53. In this chapter, we provide a comprehensive overview of the functions of mitochondrial ubiquitin ligases identified hitherto, with a special focus on cardiovascular disorders.Īuto- ubiquitination of Mdm2 Enhances Its Substrate Ubiquitin Ligase Activity* Mitochondrial ubiquitin ligase is localized in the mitochondrial outer membrane, where it plays an essential role in the regulation of mitochondrial dynamics and apoptosis. In this background, the mitochondrial ubiquitin ligase has been attracting substantial research interest in recent years. However, their dysregulation leads to a functional degradation, which results in a diverse array of common disorders, including cardiovascular disease. ![]() Mitochondrial dynamics play a critical role in cellular responses and physiological process. Mitochondrial Ubiquitin Ligase in Cardiovascular Disorders. 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 toward the autophagy pathway. In addition, p62 enhances the ubiquitinating activity of the malin-laforin E3- ubiquitin ligase complex. Binding of p62 to the malin-laforin complex allows its recognition by LC3, a component of the autophagosomal membrane. In addition, we demonstrate that the malin-laforin complex interacts with the selective autophagy adaptor sequestosome-1 (p62). 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 this work we present evidence indicating that the malin-laforin complex interacts physically and functionally with the ubiquitin conjugating enzyme E2-N (UBE2N). However, little is known about the mechanism driving malin-laforin mediated ubiquitination of its substrates. Both proteins form a functional complex, where laforin recruits specific substrates to be ubiquitinated by malin. 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. Sánchez-MartÃn, Pablo Romá-Mateo, Carlos Viana, Rosa Sanz, Pascual Ubiquitin conjugating enzyme E2-N and sequestosome-1 (p62) are components of the ubiquitination process mediated by the malin-laforin E3- ubiquitin ligase complex. Our increased understanding of ubiquitin ligase function and regulation has provided the rationale for developing E3-targeting therapeutics for the treatment of human diseases. In this review, we summarize the current progress in structure-function studies of ubiquitin ligases as well as exciting new discoveries of novel classes of E3s and diverse substrate recognition mechanisms. Recent studies have provided deeper mechanistic insights into their catalysis, activation, and regulation. Early investigations of E3s of the RING (really interesting new gene) and HECT (homologous to the E6AP carboxyl terminus) types shed light on their enzymatic activities, general architectures, and substrate degron-binding modes. At the end of a three-enzyme cascade, ubiquitin ligases mediate the transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme to specific substrate proteins. Ubiquitin E3 ligases control every aspect of eukaryotic biology by promoting protein ubiquitination and degradation. ![]() Ubiquitin Ligases: Structure, Function, and Regulation.
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