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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

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

Transcriptional Regulation by Cullin Ubiquitin Ligases

Project description:Transcriptional Regulation by Cullin Ubiquitin Ligases

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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 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.

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The tumor antigen PRAME is a substrate recognition subunit of a Cul2-based ubiquitin ligase and is associated with active NFY promoters

Project description:The human tumor antigen PRAME (Preferentially expressed antigen of melanoma) is frequently overexpressed in tumors. High PRAME levels correlate with poor clinical outcome of several cancers, but the mechanisms by which PRAME could be involved in tumorigenesis remain largely elusive. We applied protein-complex purification strategies and identified PRAME as a substrate recognition subunit of a Cullin2-based E3 ubiquitin ligase. Genome-wide chromatin immunoprecipitation experiments revealed that PRAME is specifically enriched at NF-Y promoters that are transcriptionally active, suggesting a role in gene activation. Our results are consistent with the involvement of the PRAME ubiquitin ligase complex in NF-Y-mediated transcriptional regulation. ChIP-seq binding profiles of PRAME (ChIP-seq using the preimmune serum was used as negative control), NFYA, and NFYB, and expression analysis by RNA-seq in K562 human leukemia cell line

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To identify potential ubiquitin ligases that regulate BIK1 homeostasis

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Structural mechanisms of autoinhibition and substrate recognition by the ubiquitin ligase HACE1

Project description:Ubiquitin ligases (E3s) are pivotal specificity determinants in the ubiquitin system by selecting substrates and decorating them with distinct ubiquitin signals. Structure determination of the underlying, specific E3-substrate complexes, however, has proven challenging due to their transient nature. In particular, it is incompletely understood how members of the catalytic cysteine-driven class of HECT-type ligases position substrate proteins for modification. Here we report a cryo-EM structure of the full-length human HECT-type ligase HACE1, along with solution-based conformational analyses by small-angle X-ray scattering and hydrogen-deuterium exchange mass spectrometry. Structure-based functional analyses in vitro and in cells reveal that the activity of HACE1 is stringently regulated by dimerization-induced autoinhibition. The inhibition occurs at the first step of the catalytic cycle and is thus substrate-independent. We employ mechanism-based chemical crosslinking to reconstitute a complex of activated, monomeric HACE1 with its major substrate, RAC1, visualize its structure by cryo-EM, and validate the binding mode by solution-based analyses. Our findings explain how HACE1 achieves selectivity in ubiquitinating the active, GTP-loaded state of RAC1 and establish a framework for interpreting mutational alterations of the HACE1-RAC1 interplay in disease. More broadly, this work illuminates central unexplored aspects in the architecture, conformational dynamics, regulation, and specificity of full-length HECT-type ligases.

2024-02-12 | PXD045837 | Pride

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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