The ubiquitin E3 ligase POSH regulates calcium homeostasis through spatial control of Herp (original) (raw)
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Neuralized functions as an E3 ubiquitin ligase during Drosophila development
Current Biology, 2001
The Notch pathway is a widely studied means of to the protein target via the E3 ubiquitin ligase. The E3 ubiquitin ligases are responsible for conferring target or intercellular signaling responsible for the determination of cell fate, cell differentiation, and substrate specificity. boundary formation (reviewed in [1, 2]). The main effectors of this pathway, Notch (N) and Delta (Dl), Several recent studies have implicated ubiquitination as have been shown to function as a receptor and a potential regulatory mechanism involved in N signaling. ligand, respectively. Genetic and phenotypic studies The molecular characterization of Suppressor of deltex, Su suggest that Neuralized (Neu), a RING finger (dx), which has been shown to genetically interact with protein, also plays a role within the N-Dl pathway, N, revealed that it encodes a HECT domain found in although its biochemical function is unknown. proteins that possess E3 ubiquitin ligase activity [6]. Al-Here, we show that Neu is required at the plasma though a direct role for Su (dx) in the ubiquitination of membrane for functional activity and that its RING Notch (N) has not yet been shown, a related mammalian finger domain acts as an E3 ubiquitin ligase. These protein called Itch has been shown to interact with and data suggest that the role of Neu is to target ubiquitinate N in vitro and in human Jurkat cells [7]. components of the N-Dl pathway for ubiquitination, Further genetic evidence implicating ubiquitination in N allowing for propagation and/or regulation of the signaling comes from observations that mutations in the signal. 2 and 6 subunits of the 20S proteasome cause N gainof-function phenotypes during sense organ development Addresses: *Program in Developmental Biology, † Program in Cell in Drosophila [8]. These mutations also increase the stabil-Biology,
HERCing: Structural and Functional Relevance of the Large HERC Ubiquitin Ligases
Frontiers in Physiology, 2019
Homologous to the E6AP carboxyl terminus (HECT) and regulator of chromosome condensation 1 (RCC1)-like domain-containing proteins (HERCs) belong to the superfamily of ubiquitin ligases. HERC proteins are divided into two subfamilies, Large and Small HERCs. Despite their similarities in terms of both structure and domains, these subfamilies are evolutionarily very distant and result from a convergence phenomenon rather than from a common origin. Large HERC genes, HERC1 and HERC2, are present in most metazoan taxa. They encode very large proteins (approximately 5,000 amino acid residues in a single polypeptide chain) that contain more than one RCC1-like domain as a structural characteristic. Accumulating evidences show that these unusually large proteins play key roles in a wide range of cellular functions which include neurodevelopment, DNA damage repair, and cell proliferation. To better understand the origin, evolution, and function of the Large HERC family, this minireview provides with an integrated overview of their structure and function and details their physiological implications. This study also highlights and discusses how dysregulation of these proteins is associated with severe human diseases such as neurological disorders and cancer.
Developmental Cell, 2001
other proteins that function as part of multiprotein complexes, suggesting that Neur may as well. Second, we 2 Salk Institute for Biological Studies San Diego, California 92186 observed that Neur deleted for the RING finger (Neur⌬RF) behaved as a strong dominant-negative protein, indicating that this domain is essential for normal Neur function. Third, we observed that ectopic Neur and Neur⌬RF af-Summary fected multiple neur-independent, N pathway-regulated processes, suggesting that Neur regulates the activity The Drosophila gene neuralized (neur) has long been recognized to be essential for the proper execution of of a core member of the N pathway. Finally, we determined that epitope-tagged Neur associates primarily a wide variety of processes mediated by the Notch (N) pathway, but its role in the pathway has been elusive.
BioE3 identifies specific substrates of ubiquitin E3 ligases
Nature Communications, 2023
Hundreds of E3 ligases play a critical role in recognizing specific substrates for modification by ubiquitin (Ub). Separating genuine targets of E3s from E3-interactors remains a challenge. We present BioE3, a powerful approach for matching substrates to Ub E3 ligases of interest. Using BirA-E3 ligase fusions and bioUb, site-specific biotinylation of Ub-modified substrates of particular E3s facilitates proteomic identification. We show that BioE3 identifies both known and new targets of two RING-type E3 ligases: RNF4 (DNA damage response, PML bodies), and MIB1 (endocytosis, autophagy, centrosome dynamics). Versatile BioE3 identifies targets of an organellespecific E3 (MARCH5) and a relatively uncharacterized E3 (RNF214). Furthermore, BioE3 works with NEDD4, a HECT-type E3, identifying new targets linked to vesicular trafficking. BioE3 detects altered specificity in response to chemicals, opening avenues for targeted protein degradation, and may be applicable for other Ub-likes (UbLs, e.g., SUMO) and E3 types. BioE3 applications shed light on cellular regulation by the complex UbL network. Protein ubiquitination is conserved in all eukaryotes and plays crucial roles in almost all cellular processes. Ubiquitin (Ub) conjugation is coordinated by a three-step enzymatic cascade, which can be reversed by the action of deubiquitinating enzymes (DUBs). This cycle is conserved among the different ubiquitin-like proteins (UbLs), each using their own set of enzymes, often depicted as E1 (activating), E2 (conjugating), E3 (ligating), and DUBs. Specificity of ubiquitin toward particular targets is achieved as the cycle progresses. In humans, two Ub E1 enzymes, around 40 E2s and about 700 E3 ligases cooperate to selectively target thousands of substrates 1. The question of how substrate specificity is achieved might benefit from a compendium of targets for specific E3 ligases. Ub E3 ligases are subdivided into categories, according to shared domains and modes of action for substrate modification 2. The main family covers more than 600 RING (Really Interesting New Gene) type Ub E3 ligases. The RING domain allows the direct transfer of Ub from the E2 to the target protein by placing them in close proximity 3. To function, some RING E3 ligases (e.g., RNF4; RING Finger protein 4), dimerize through their RING domain 4 , or create multi-subunit complexes, (e.g., Cullin RING Ligases). CRLs can recognize diverse targets with specificity by forming complexes with >300 different substrate receptors 2. In the case of HECT (Homology to E6AP C Terminus) and RBR (RING-Between-RING) E3 ligases, a covalent E3~Ub thioester
Cell regulation by phosphotyrosine-targeted ubiquitin ligases
Molecular and cellular biology, 2015
Three classes of E3 ubiquitin ligases, members of the Cbl, Hakai and SOCS families, stimulate the ubiquitination of phosphotyrosine-containing proteins, including receptor and non-receptor tyrosine kinases and their phosphorylated substrates. Because ubiquitination frequently routes proteins for degradation by the lysosome or proteasome, these E3 ligases are able to potently inhibit tyrosine kinase signaling. Their loss or mutational inactivation can contribute to cancer, autoimmunity or endocrine disorders such as diabetes. However, these ligases also have biological functions that are independent of their ubiquitination activity. Here we review relevant literature and then focus on more recent developments in understanding the structures, substrates and pathways through which the phosphotyrosine-specific ubiquitin ligases regulate diverse aspects of cell biology.