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A degron-mimicking molecular glue drives CRBN homo-dimerization and degradation

ABSTRACT: Cereblon (CRBN) is a ubiquitin ligase widely harnessed for targeted protein degradation. We report the discovery of a molecular glue that drives CRBN homo-dimerization and subsequent fast, potent, and selective CRBN degradation by the ubiquitin proteasome system. The structure of the complex reveals a unique mechanism whereby two molecular glues assemble into a helix-like structure and drive ternary complex formation by mimicking a protein degron in trans.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Monocyte, Ascites

SUBMITTER: Despoina Kapsitidou

LAB HEAD: Debora Bonenfant

PROVIDER: PXD065335 | Pride | 2025-09-08

REPOSITORIES: Pride

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	PX_DEG_00096_2025_ECL03_MS3_CRBN_Fct.mzML	Mzml
	PX_DEG_00096_2025_Experimental_TMT_Design.xlsx	Xlsx
	PX_DEG_00096_2025_Fct.msf	Msf
	PX_DEG_00096_2025_Fct.mzid	Mzid
	PX_DEG_00096_2025_Fct01_0615.raw	Raw

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A degron-mimicking molecular glue drives CRBN homo-dimerization and degradation

Project description:Cereblon (CRBN) is a ubiquitin ligase widely harnessed for targeted protein degradation. We report the discovery of a molecular glue that drives CRBN homo-dimerization and subsequent fast, potent, and selective CRBN degradation by the ubiquitin proteasome system. The structure of the complex reveals a unique mechanism whereby two molecular glues assemble into a helix-like structure and drive ternary complex formation by mimicking a protein degron in trans.

2025-09-08 | PXD060261 | Pride

Discovery of a Small Molecule Degrader that Sustains pan-AKT Degradation and Downstream Signaling Effects

Project description:The PI3K/AKT signaling cascade is one of the most commonly dysregulated pathways in cancer, with over 50% of tumors showing aberrant AKT hyperactivation. Although potent small molecule AKT inhibitors have entered clinical trials, robust and durable therapeutic responses have not been observed. As an alternative strategy to target AKT, we report the development of INY-03-041, a pan-AKT degrader consisting of GDC-0068, an AKT inhibitor, conjugated to lenalidomide, a recruiter of the E3 ubiquitin ligase, Cereblon (CRBN). INY-03-041 induced potent degradation of all three AKT isoforms and displayed enhanced anti-proliferative effects relative to GDC-0068. Notably, INY-03-041 promoted sustained AKT degradation and inhibition of downstream signaling effects for up to 96 hours, even after compound washout. Overall, our findings suggest that AKT degradation may provide prolonged pharmacological effects compared to inhibition, and highlight the potential advantages of AKT-targeted degradation.

2019-11-27 | PXD015207 | Pride

DNAAF9 interactome from human airway epithelial cells

Project description:Biogenesis of motile cilia in multiciliated cells (MCCs) is coupled to large-scale biosynthesis of force generating dynein motors. Shulin inhibits pre-assembled ODA (outer dynein arm) motors by packaging them into a closed conformation preventing aberrant off-target interactions with cellular microtubules in multiciliated Tetrahymena cells and co-localises with them in growing cilia. How packaged ODAs engage the Intraflagellar Transport machinery (IFT) to transit from the cytoplasm into growing cilia remains unclear. The mechanism of Shulin’s release for ODA activation inside cilia is also poorly resolved. Using proteomics, we establish links between DNAAF9 (human Shulin) and mammalian ODAs, the anterograde IFT-B complex and a ciliary small GTPase called ARL3. Based on our findings, we propose that Shulin/DNAAF9 enforces ODA inhibition to aid their unimpeded trafficking from the cytoplasm into growing multicilia via IFT and once inside the ciliary compartment, ARL3-GTP competes for a binding site to destabilise the ODA-Shulin complex thereby promoting ODA motor activation.

2025-07-31 | PXD052722 | Pride

N2 versus octr-1 shotgun proteomics nano MS/MS

Project description:by using a mass spectrometry-based quantitative proteomics approach, we discovered that OCTR-1 regulates innate immunity by suppressing translation and the unfolded protein response (UPR) pathways at the protein level.

2016-12-22 | PXD004173 | Pride

Multi-platforms approach for plasma: complementarity of Olink PEA technology to DIA-based mass spectrometry-based protein profiling

Project description:Plasma proteome is the ultimate target for the biomarker discovery. It stores an endless amount of information on the pathophysiological status of a living organism, which however is still difficult to comprehensively access. The high structural complexity of the plasma proteome can be addressed by using a system-wide and unbiased tool such as mass spectrometry (LC-MS/MS) or highly sensitive targeted immunoassays as Olink Proximity Extension Assays. We have tested the performance of LC-MS/MS in data –dependent and -independent acquisition modes and Olink PEA to measure circulating plasma proteins in 173 human plasma samples from a southern Germany population-cohort. More than 300 proteins were measured by both LC-MS/MS approaches, mainly including high abundance functional plasma proteins. By using the Olink PEA technology we measured 728 plasma proteins, covering a broad dynamic range with high sensitivity down to pg/ml levels. We found 35 overlapping proteins in all three analytical platforms, predominantly secreted and highly abundant in plasma. The complementarity of the platforms was assessed by veryfing the reproducibility of data distributions, statistical correlation of measurements and gender-based differential expression analysis. Our work highlights the limitations and the advantages of both targeted and untargeted approaches and prove their complementarity. We demostrated that by combining the results of the three platforms we gain in depth proteome coverage as well as biological insights.

2022-03-10 | PXD020261 | Pride

Maternal iron deficiency modulates placental transcriptome and proteome in mid-gestation of mouse pregnancy

Project description:Background: Maternal iron deficiency (ID) is associated with poor pregnancy and fetal outcomes. The effect is thought to be mediated by the placenta but there is no comprehensive assessment of placental response to maternal ID. Additionally, whether the influence of maternal ID on the placenta differs by fetal sex is unknown. Objectives: Our primary aim was to identify gene and protein signatures of ID mouse placentas at mid-gestation. A secondary objective was to profile the expression of iron genes in mouse placentas across gestation. Methods: We used a real-time PCR based array to determine the mRNA expression of all known iron genes in mouse placentas at embryonic day (E) 12.5, E14.5, E16.5, and E19.5 (n=3 placentas/time point). To determine the effect of maternal ID, we performed RNA sequencing and proteomics in male and female placentas from ID and iron adequate mice at E12.5 (n=8 dams/diet). Results: In female placentas, six genes including transferrin receptor (Tfrc) and solute carrier family 11 member 2 were significantly changed by maternal ID. An additional 154 genes were altered in male ID placentas. Proteomic analysis quantified 7662 proteins in the placenta. Proteins translated from iron responsive element (IRE) containing mRNAs were altered in abundance; ferritin and ferroportin 1 decreased while TFRC increased in ID placenta. Less than 4% of the significantly altered genes in ID placentas occurred both at the transcriptional and translational levels. Conclusions: Our data demonstrate that the impact of maternal ID on placental gene expression in mice is limited in scope and magnitude at mid-gestation. We provide strong evidence for IRE-based transcriptional and translational coordination of iron gene expression in the mouse placenta. Finally, we discover sexually dimorphic effects of maternal ID on placental gene expression, with more genes and pathways altered in male compared with female mouse placentas.

2021-03-12 | PXD023454 | Pride

Proteomics on sera of mice following local high-dose heart irradiation

Project description:Background and Purpose: Cardiotoxicity is a well-known adverse effect of radiation therapy. Measurable abnormalities in the heart function indicate advanced and often irreversible heart damage. Therefore, early detection of cardiac toxicity is necessary to delay and alleviate the development of the disease. The present study investigated long-term serum proteome alterations following local heart irradiation using a mouse model with the aim to detect biomarkers of radiation-induced cardiac toxicity. Materials and Methods: Serum samples from C57BL/6J mice were collected 20 weeks after local heart irradiation with 8 Gy or 16 Gy X-ray; the controls were sham-irradiated. The samples were analyzed by quantitative proteomics based on data-independent acquisition mass spectrometry. The proteomics data were further investigated using bioinformatics and ELISA. Results: The analysis showed radiation-induced changes in the level of several serum proteins involved in the acute phase response, inflammation and cholesterol metabolism. We found significantly enhanced expression of pro-inflammatory cytokines (TNF-, TGF-, IL-1 and IL-6) in the serum of the irradiated mice. The level of free fatty acids, total cholesterol, low density lipoprotein (LDL) and oxidized LDL was increased whereas that of high density lipoprotein was decreased by irradiation. Conclusions: This study provides information on systemic effects of heart irradiation. It elucidates a radiation fingerprint in the serum that may be used to elucidate adverse cardiac effects after radiation therapy.

2021-09-10 | PXD024446 | Pride

Carotid endarterectomy tissue and tissue-derived extracellular vesicle proteomes from symptomatic and asymptomatic patients

Project description:This study sought to compare how the tissue extracellular vesicle proteome of carotid atherosclerotic plaques differs between symptomatic and asymptomatic patients. Carotid arteries samples were collected from symptomatic and asymptomatic patients undergoing endarterectomies. The specimen was grossly dissected in to 1) the maximally diseased plaque zone and 2) adjacent marginal zones. Extracellular vesicles were isolated from these matched tissue regions from each specimen using collagenase digestion, size exclusion chromatography, and density gradient ultracentrifugation. Label-free proteomics was performed on both the intact tissues (N=5) and the tissue derived EVs (N=23: symptomatic patients N=13, asymptomatic patients N=10).

2025-06-30 | PXD052938 | Pride

Activity based proteome profiling of serum serine hydrolases: application in pediatric abusive head trauma

Project description:Purpose: Traumatic brain injury (TBI), including pediatric abusive head trauma (AHT), is the leading cause of death and disability in children and young adults worldwide. The current understanding of trauma-induced molecular changes in the brain of human subjects with intracranial haemorrhage (ICH) remains inadequate and requires further investigation to improve the outcome and management of TBI in the clinic. Calcium-mediated damage at the site of brain injury has been shown to activate several catalytic enzymes. Experimental design: Serine hydrolases (SHs) are major catalytic enzymes involved in the biochemical pathways of blood coagulation, systemic inflammation and neuronal signaling. Here we investigated activity-based protein profiling (ABPP) by measuring the activity status of SH enzymes in the serum of infants with severe ICH as a consequence of AHT or atraumatic infants who died of sudden infant death syndrome (SIDS). Results: Our proof-of-principle study revealed significantly reduced physiological activity of dozens of metabolic SHs in the serum of infants with severe AHT compared to the SIDS group, with some of the enzymes being related to neurodevelopment and basic brain metabolism.

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2020-10-19 | PXD021238 | Pride