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Structural basis for substrate recognition and chemical inhibition of oncogenic MAGE ubiquitin ligases

ABSTRACT: Structural basis for substrate recognition and chemical inhibition of oncogenic MAGE ubiquitin ligases

PROVIDER: PRJNA624321 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11523534_1.fastq.gz	Fastqsanger.gz
	SRR11523534_2.fastq.gz	Fastqsanger.gz
	SRR11523535_1.fastq.gz	Fastqsanger.gz
	SRR11523535_2.fastq.gz	Fastqsanger.gz
	SRR11523536_1.fastq.gz	Fastqsanger.gz

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Structural basis for substrate recognition and chemical inhibition of oncogenic MAGE ubiquitin ligases

Project description:Testis-restricted melanoma antigen (MAGE) proteins are frequently hijacked in cancer and play a critical role in tumorigenesis. MAGEs assemble with E3 ubiquitin ligases and function as substrate adaptors that direct the ubiquitination of novel targets, including key tumor suppressors. However, how MAGEs recognize their targets is unknown and has impeded development of MAGE-directed therapeutics. Here, we report the structural basis for substrate recognition by MAGE ubiquitin ligases. Biochemical analysis of the degron motif recognized by MAGE-A11 and the crystal structure of MAGE-A11 bound to the PCF11 substrate uncovered a conserved substrate binding cleft (SBC) in MAGEs. Mutation of the SBC disrupted substrate recognition by MAGEs and blocked MAGE-A11 oncogenic activity. A chemical screen for inhibitors of MAGE-A11:substrate interaction identified 4-aminoquniolines as potent inhibitors of MAGE-A11 that show selective cytotoxicity. These findings provide important insights into the large family of MAGE ubiquitin ligases and identify approaches for development of cancer-specific therapeutics.

2020-08-15 | GSE148458 | GEO

Structural basis for substrate recognition and chemical inhibition of oncogenic MAGE ubiquitin ligases.

Project description:Testis-restricted melanoma antigen (MAGE) proteins are frequently hijacked in cancer and play a critical role in tumorigenesis. MAGEs assemble with E3 ubiquitin ligases and function as substrate adaptors that direct the ubiquitination of novel targets, including key tumor suppressors. However, how MAGEs recognize their targets is unknown and has impeded the development of MAGE-directed therapeutics. Here, we report the structural basis for substrate recognition by MAGE ubiquitin ligases. Biochemical analysis of the degron motif recognized by MAGE-A11 and the crystal structure of MAGE-A11 bound to the PCF11 substrate uncovered a conserved substrate binding cleft (SBC) in MAGEs. Mutation of the SBC disrupted substrate recognition by MAGEs and blocked MAGE-A11 oncogenic activity. A chemical screen for inhibitors of MAGE-A11:substrate interaction identified 4-Aminoquinolines as potent inhibitors of MAGE-A11 that show selective cytotoxicity. These findings provide important insights into the large family of MAGE ubiquitin ligases and identify approaches for developing cancer-specific therapeutics.

| S-EPMC7529893 | biostudies-literature

Transcriptional Regulation by Cullin Ubiquitin Ligases

Project description:Transcriptional Regulation by Cullin Ubiquitin Ligases

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To identify potential ubiquitin ligases that regulate BIK1 homeostasis

Project description:To identify potential ubiquitin ligases that regulate BIK1 homeostasis

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To identify potential ubiquitin ligases that regulate BIK1 homeostasis

Project description:To identify potential ubiquitin ligases that regulate BIK1 homeostasis,A total amount of 3 µg RNA per sample was used as input material for the RNA sample preparations. Sequencing libraries were generated using NEBNext® Ultra™ RNA Library Prep Kit for Illumina® (NEB, USA) following manufacturer’s recommendations and index codes were added to attribute sequences to each sample. We using an optimized data analysis workflow,

2023-06-14 | GSE227628 | GEO

Combinatorial mapping of E3 ubiquitin ligases to their target substrates

Project description:E3 ubiquitin ligases (E3s) confer specificity of protein degradation through the recognition of specific target substrates for ubiquitination and subsequent degradation, making E3s attractive candidates for drug development. There are over 600 annotated E3s in the human genome, yet the vast majority have no known substrate proteins, due in part to the limited scalability of methods to evaluate the vast number of potential E3-substrate interactions. To address this, we developed COMET (Combinatorial Mapping of E3 Targets), a combinatorial framework that can test the role of many specific E3s in regulating the abundance of many specific substrates, within the context of a single experiment. As a proof-of-concept, we applied COMET to identify specific E3 subunits of the SCF ubiquitin ligase complex that mediate the degradation of target substrates, including short-lived transcription factors (TFs). Our data suggest that many E3-substrate relationships are complex rather than simple 1:1 associations. Further, we provide computational models of E3-substrate interactions from our screen. Looking forward, we anticipate that COMET can be further scaled to enable comprehensive mapping of regulators of protein stability to their target substrates

2025-02-07 | GSE234621 | GEO

Combinatorial mapping of E3 ubiquitin ligases to their target substrates

Project description:Combinatorial mapping of E3 ubiquitin ligases to their target substrates

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SIAH ubiquitin E3 ligases as modulators of inflammatory gene expression

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Repurposing E3 ubiquitin ligases as cell surface protein degraders using Proteolysis Targeting Antibodies

Project description:The majority of current therapeutics targeting plasma membrane receptors function by antagonizing ligand binding or enzymatic activities. Typical mammalian proteins, however, consist of multiple domains executing discrete but coordinated activities, and saturating inhibition of one functional domain often incompletely suppresses the totality of the protein’s function. Recent work on targeted protein degradation technologies including Proteolysis Targeting Chimeras (PROTACs) has highlighted clinically important distinctions between target inhibition and target degradation. However, the generation of heterobifunctional compounds requiring linkage of two small molecules, each with high affinity for their targets, is highly complex, particularly with respect to achieving oral bioavailability. Here we describe the development of Proteolysis Targeting Antibodies (PROTABs) that tether cell-surface E3 ubiquitin ligases to transmembrane proteins, resulting in target ubiquitination and subsequent degradation. PROTAB-mediated degradation drives deeper pathway inhibition than inhibitory antibodies and is functional in vivo. The scope of this technology is also demonstrated through the identification of additional cell surface E3 ubiquitin ligases that can function as “on demand” degraders of various cell surface proteins. The generality of this approach enables tissue-selective degradation, as suggested by the Wnt-responsive ligases RNF43 and ZNRF3. Furthermore, through engineering of various optimized antibody formats, we offer insights on the ground rules governing optimal target degradation. Taken together, this work describes a strategy for the rapid development of potent, bioavailable and tissue selective degradation of cell surface proteins.

2022-07-21 | GSE208372 | GEO

SIAH ubiquitin E3 ligases as modulators of inflammatory gene expression

Project description:The functionally redundant ubiquitin E3 ligases SIAH1 and SIAH2 have been implicated in the regulation of several processes, but their role in inflammatory signaling and gene expression remains unclear. Here we have downregulated the expression of both SIAH proteins with specific siRNAs and investigated the functional consequences for IL-1α-induced gene expression and the signaling pathways activating NF-κB and AP1. The knockdown of SIAH1/2 had no significant impact on IL-1α-induced activation of NF-κB and MAPK signaling pathways, but modulated the expression of approximately one third of IL-1α-regulated genes. Most of the proteins encoded by SIAH1/2-regulated genes form a regulatory network of proinflammatory factors. Thus SIAH1/2 proteins function as variable rheostats that control the amplitude of inflammatory gene expression.

2022-02-01 | GSE179190 | GEO

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