FBXO38 is dispensable for PD-1 regulation

EMBO Reports, Год журнала: 2024, Номер unknown

Опубликована: Сен. 12, 2024

Abstract SKP1-CUL1-F-box protein (SCF) ubiquitin ligases are versatile complexes that mediate the ubiquitination of substrates. The direct substrate recognition relies on a large family F-box-domain-containing subunits. One these receptors is FBXO38, which encoded by gene found mutated in families with early-onset distal motor neuronopathy. SCF FBXO38 ligase controls stability ZXDB, nuclear factor associated centromeric chromatin CENP-B. Loss mice results growth retardation and defects spermatogenesis characterized deregulation Sertoli cell transcription program compromised centromere integrity. Moreover, it was reported mediates degradation PD-1, key immune-checkpoint inhibitor T cells. Here, we have re-addressed link between PD-1 proteolysis. Our data do not support notion directly or indirectly abundance

Язык: Английский

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DegronMD: Leveraging Evolutionary and Structural Features for Deciphering Protein-Targeted Degradation, Mutations, and Drug Response to Degrons

Molecular Biology and Evolution, Год журнала: 2023, Номер 40(12)

Опубликована: Ноя. 22, 2023

Protein-targeted degradation is an emerging and promising therapeutic approach. The specificity of the maintenance cellular homeostasis are determined by interactions between E3 ubiquitin ligase signals, known as degrons. human genome encodes over 600 ligases; however, only a small number targeted degron instances have been identified so far. In this study, we introduced DegronMD, open knowledgebase designed for investigation degrons, their associated dysfunctional events, drug responses. We revealed that degrons evolutionarily conserved tend to occur near sites protein translational modifications, particularly in regions disordered structure higher solvent accessibility. Through pattern recognition machine learning techniques, constructed degrome landscape across proteome, yielding 18,000 new degradation. Furthermore, dysfunction disrupts process leads abnormal accumulation proteins; with various types cancers. Based on estimated phenotypic changes induced somatic mutations, systematically quantified assessed impact mutations function pan-cancers; these results helped build global mutational map degrome, including 89,318 actionable may induce disrupt pathways. Multiomics integrative analysis unveiled 400 resistance events functional accessible at https://bioinfo.uth.edu/degronmd, useful resource explore biological mechanisms, infer degradation, assist discovery design

Язык: Английский

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Role of Post-Translational Modifications in Colorectal Cancer Metastasis

Cancers, Год журнала: 2024, Номер 16(3), С. 652 - 652

Опубликована: Фев. 3, 2024

Colorectal cancer (CRC) is one of the most common malignant tumors digestive tract. CRC metastasis a multi-step process with various factors involved, including genetic and epigenetic regulations, which turn out to be serious threat patients. Post-translational modifications (PTMs) proteins involve addition chemical groups, sugars, or specific residues, fine-tunes protein’s stability, localization, interactions orchestrate complicated biological processes. An increasing number recent studies suggest that dysregulation PTMs, such as phosphorylation, ubiquitination, glycosylation, play pivotal roles in cascade. Here, we summarized advances role post-translational diverse aspects its detailed molecular mechanisms. Moreover, drugs targeting PTMs their cooperation other anti-cancer drugs, might provide novel targets for treatment improve therapeutic efficacy, were also discussed.

Язык: Английский

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The hGID^GID4E3 ubiquitin ligase complex targets ARHGAP11A to regulate cell migration

Life Science Alliance, Год журнала: 2024, Номер 7(12), С. e202403046 - e202403046

Опубликована: Окт. 10, 2024

The human CTLH/GID (hGID) complex emerged as an important E3 ligase regulating multiple cellular processes, including cell cycle progression and metabolism. However, the range of biological functions controlled by hGID remains unexplored. Here, we used proximity-dependent biotinylation (BioID2) to identify proteins interacting with complex, among them, substrate candidates that bind GID4 in a pocket-dependent manner. Biochemical assays revealed binds ubiquitinates ARHGAP11A, thereby targeting this RhoGAP for proteasomal degradation. Indeed, depletion or impeding binding pocket PFI-7 inhibitor stabilizes ARHGAP11A protein amounts, although it carries no functional N-terminal degron. Interestingly, inactivation impairs motility directed movement increasing levels at periphery, where inactivates RhoA. Together, identified wide substrates uncovered unique function migration ARHGAP11A.

Язык: Английский

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MetaDegron: multimodal feature-integrated protein language model for predicting E3 ligase targeted degrons

Briefings in Bioinformatics, Год журнала: 2024, Номер 25(6)

Опубликована: Сен. 23, 2024

Abstract Protein degradation through the ubiquitin proteasome system at spatial and temporal regulation is essential for many cellular processes. E3 ligases signals (degrons), sequences they recognize in target proteins, are key parts of ubiquitin-mediated proteolysis, their interactions determine specificity maintain homeostasis. To date, only a limited number targeted degron instances have been identified, properties not yet fully characterized. tackle on this challenge, here we develop novel deep-learning framework, namely MetaDegron, predicting ligase by integrating protein language model comprehensive featurization strategies. Through extensive evaluations using benchmark datasets comparison with existing method, such as Degpred, demonstrate superior performance MetaDegron. Among functional features, MetaDegron allows batch prediction degrons 21 ligases, provides annotations visualization multiple degron-related structural physicochemical features. freely available http://modinfor.com/MetaDegron/. We anticipate that will serve useful tool clinical translational community to elucidate mechanisms homeostasis, cancer research, drug development.

Язык: Английский

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Predictive modeling for ubiquitin proteins through advanced machine learning technique

Heliyon, Год журнала: 2024, Номер 10(12), С. e32517 - e32517

Опубликована: Июнь 1, 2024

Ubiquitination is an essential post-translational modification mechanism involving the ubiquitin protein's bonding to a substrate protein. It crucial in variety of physiological activities including cell survival and differentiation, innate adaptive immunity. Any alteration system leads development various human diseases. Numerous researches show highly reversibility dynamic system, making experimental identification quite difficult. To solve this issue, article develops model using machine learning approach, tending improve protein prediction precisely. We deeply investigate ubiquitination data that proceed through different features extraction methods, followed by classification. The evaluation assessment are conducted considering Jackknife tests 10-fold cross-validation. proposed method demonstrated remarkable performance terms 100 %, 99.88 99.84 % accuracy on Dataset-I, Dataset-II, Dataset-III, respectively. Using test, achieves 99.91 99.99 for Dataset-II This analysis concludes outperformed state-of-the-arts identify sites helpful current clinical therapies. source code datasets will be made available at Github.

Язык: Английский

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A quantitative intracellular peptide binding assay reveals recognition determinants and context dependence of short linear motifs

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 1, 2024

ABSTRACT Transient protein-protein interactions play key roles in controlling dynamic cellular responses. Many examples involve globular protein domains that bind to peptide sequences known as Short Linear Motifs (SLiMs), which are enriched intrinsically disordered regions of proteins. Here we describe a novel functional assay for measuring SLiM binding, called Systematic Intracellular Motif Binding Analysis (SIMBA). In this method, binding foreign domain its cognate allows yeast cells proliferate by blocking growth arrest signal. A high-throughput application the SIMBA method involving competitive and deep sequencing provides rapid quantification relative strength thousands sequence variants, comprehensive interrogation features control their recognition potency. We show multiple distinct classes SLiM-binding can be analyzed peptides vivo correlates with biochemical affinities measured vitro. Deep mutational scanning high-resolution definitions motif determinants reveals how variations at non-core positions modulate strength. Furthermore, parent human tankyrase ARC or YAP WW identifies modes uncovers context effects preferred residues one position depend on elsewhere. The findings establish fast incisive approach interrogating via massively parallel protein-peptide vivo.

Язык: Английский

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High resolution profiling of cell cycle-dependent protein and phosphorylation abundance changes in non-transformed cells

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 21, 2024

Abstract The cell cycle governs a precise series of molecular events, regulated by coordinated changes in protein and phosphorylation abundance, that culminates the generation two daughter cells. Here, we present proteomic phosphoproteomic analysis human hTERT-RPE-1 cells using deep quantitative mass spectrometry isobaric labelling. Through analysing non-transformed cells, improving temporal resolution coverage key regulators, dataset cycle-dependent site oscillation offers foundational reference for investigating regulation. These data reveal uncharacterised regulatory intricacies including proteins sites exhibiting previously unreported oscillation, novel targeted degradation during mitotic exit. Integrated with complementary resources, our link abundance dynamics to functional are accessible through Cell Cycle database (CCdb), an interactive web-based resource community.

Язык: Английский

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Turnover of RNA-binding Proteins and MicroRNAs by intrinsically disordered region-directed ZSWIM8 ubiquitin ligase during brain development

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Янв. 28, 2024

Abstract Widely present in mammalian proteomes, intrinsically disordered regions (IDRs) proteins play important biological functions by conferring structural flexibility and mediating biomolecular interactions. IDR-containing proteins, including many RNA-binding (RBPs), are prone to misfolding aggregation must be constantly monitored. Here we show that the conserved ZSWIM8-type Cullin-RING ubiquitin ligase (CRL ZSWIM8 ) is a master regulator of such during brain development. selects its substrates via an IDR-dependent mechanism, deletion causes aberrant accumulation numerous RBPs AGO2 ELAV1 neonatal brains. Furthermore, ubiquitination triggered microRNA binding, leading target-directed degradation (TDMD) MiR7. Dysregulation MiR7 absence results defects oligodendrocyte maturation functions. Together, our findings have demonstrated that, utilizing variable target-recognition strategies, controls abundance conformationally flexible miRNA metabolism essential for Teaser A quality ensure

Язык: Английский

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Molecular insights into degron recognition by CRL5ASB7 ubiquitin ligase

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Июль 22, 2024

Abstract The ankyrin (ANK) SOCS box (ASB) family, encompassing ASB1–18, is the largest group of substrate receptors cullin 5 Ring E3 ubiquitin ligase. Nonetheless, mechanism recognition by ASB family proteins has remained largely elusive. Here we present crystal structure ASB7-Elongin B-Elongin C ternary complex bound to a conserved helical degron. ASB7 employs its ANK3-6 form an extended groove, effectively interacting with internal α-helix-degron through network side-chain-mediated electrostatic and hydrophobic interactions. Our structural findings, combined biochemical cellular analyses, identify key residues degron motif required for their recognition. This will facilitate identification additional physiological substrates providing defined screening. Furthermore, insights provide basis rational design compounds that can specifically target disrupting interaction cognate

Язык: Английский

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