June 2024 Edition: Overcoming the limitations of existing degrons

June 2024 Edition: Overcoming the limitations of existing degrons

Check out the latest in proteomics research, including the latest publications featuring IonOpticks' famed Aurora Series products.

Overcoming the limitations of existing degrons

For my top pick from June, I've highlighted a study that presents a new workflow for developing degrons that enable specific elimination of target proteins.

In conditional protein degradation, researchers have faced the limitations of existing degrons, which are typically over 100 amino acids long or triggered by small molecules with substantial off-target effects. However, in a recent study by Mercer et al., published in Science, the authors present a novel solution to this challenge utilising continuous evolution of degrons.

The researchers developed a novel phage-assisted continuous evolution (PACE) platform for generating molecular glue complexes. Using this platform, they evolved a compact 36-amino acid zinc finger (ZF) degron, termed SD40. This degron binds to the ubiquitin ligase effector, cereblon, in complex with PT-179, an IMiD derivative that does not induce degradation of off-target proteins. The small size of SD40 facilitates efficient and precise in-frame insertions in target protein-coding genes within human cells through prime editing. This enables minimally disruptive studies of endogenous proteins produced from genes that retain their native regulatory environments and functions.

By using an Aurora Ultimate UHPLC column, the researchers were able to achieve deep, quantitative proteome coverage and demonstrate the specificity of PT-179 and the efficacy of SD40, which were both critical aspects of this study.

To gain mechanistic insights into SD40's activity and specificity, as well as its molecular basis, the researchers solved cryo-electron microscopy structures of SD40 in complex with PT-179 bound to cereblon. This revealed that SD40 engages with the IMiD-binding C-terminal domain of CRBN and also creates a substantial interface with its N-terminal domain.

This study not only establishes a powerful system to continuously evolve molecular glue complexes but also introduces compact ZF tags that overcome the shortcomings of existing degrons. This breakthrough addresses a longstanding challenge in the field, enabling more precise and specific modulation of endogenous protein levels.

Dr Jarrod Sandow

Head of Product Development, IonOpticks


Check out Jarrod's top pick in more detail:

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LATEST PAPERS


Thunder-DDA-PASEF enables high-coverage immunopeptidomics and is boosted by MS 2 Rescore with MS 2 PIP timsTOF fragmentation prediction model

A study that was previously a pre-print in?Research Square?has now been peer-reviewed and published in Nature Communications.?Identifying ligands of the major histocompatibility complex (MHC) or human leukocyte antigen (HLA) is crucial for developing vaccines and immunotherapies. However, LC-MS immunopeptidomics faces challenges due to the...

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Preprint: Longitudinal proteomic profiling of T cell differentiation in vivo unveils dynamic proteome remodeling

The first in vivo longitudinal proteomic profiling of antigen-specific CD8 T cells during both acute and chronic viral infections is presented by Beusch et al. in this new study, pre-printed in BioRxiv.?Using the well-established lymphocytic choriomeningitis virus (LCMV) mouse model, researchers compared the proteomes of T cells in mice infected with...

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Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer

Wasko et al. investigate the pharmacology and anti-tumor activity of RMC-7977, a multi-selective inhibitor targeting active, GTP-bound RAS family proteins (a RAS(ON) inhibitor), in preclinical models of pancreatic ductal adenocarcinoma (PDAC). RMC-7977 consistently and significantly inhibited...

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In June, our columns were featured in not one, not two, but three new application notes.?

Bruker presented an enhanced single-cell proteomics workflow as well as a new data acquisition method tailored to glycoproteomics. Evosep presented new methods that enhance the performance for high-sensitivity LC-MS proteomics.


S I N G L E C E L L P R O T E O M I C S

plexDIA for scalable single cell analysis – improving quantification and sensitivity by TIMS separation?

Bruker's enhanced single-cell proteomics workflow is based on plexDIA (multiplexed data-independent acquisition), which was developed by Nikolai Slavov's lab at Parallel Squared Technology Institute. It significantly reduces spectral interference, enhancing both MS1 and MS2 spectra quality.

Combining a timsTOF Ultra with an Aurora Ultimate 25x75 column, this method enabled an average of 14.5 data points per peak with a throughput of 96 samples per day, far surpassing the typical 3-4 data points in standard methods and 32 samples per day in label-free analysis.

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G L Y C O P R O T E O M I C S

Leveraging online parallel accumulation, serial fragmentation (PASEF) in timsTOF mass spectrometers for high sensitivity, high throughput bottom-up N-glycoproteome analysis with the glyco-PASEF method

Discover the latest advancements in glycopeptide sequencing with?Bruker’s timsTOF instruments. Optimized with our Aurora Ultimate 25x75 column, this new glycoproteomics method achieves outstanding depth and sensitivity, while mainting higher throughput. Leveraging ion mobility and stepped collision energy (SCE) fragmentation, the timsTOF enables high-quality spectra and rapid glycopeptide detection, even with short chromatography gradients.

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E V O S E P W H I S P E R M E T H O D S

Whisper Zoom drives scalable workflows for high-sensitivity applications through standardization and ease-of-use

The new Whisper Zoom methods, utilizing IonOpticks' Aurora Rapid 5 cm x 75 um column, enhance performance for high-sensitivity LC-MS proteomics by increasing sensitivity and throughput to up to 120 samples per day. With intra-instrument variability of less than 5 seconds and inter-instrument variability of less than 16 seconds, it supports new projects and accelerates ongoing collaborations, advancing the field of proteomics toward new discoveries and innovations.

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2024 EVENT CALENDAR


2024 International Mass Spectrometry Conference (IMSC 2024)

Melbourne, Australia

17-23 August, 2024

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5th European Single-cell Conference (ESCP 2024)

Vienna, Austria

27-29 August, 2024

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Conference on Mass Spectrometry and Proteomic Analysis (SMAP) 2024

Lille, France

16-19 September, 2024

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23rd Human Proteome Organization World Congress (HUPO 2024)

Dresden, Germany

20-24 October, 2024

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International Single-Cell Mass Spectrometry Conference (iSCMS) 2024

Copenhagen, Denmark

26-28 October, 2024

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