Picotti Lab

Picotti Lab

@picottilab.bsky.social

The official Bluesky account of the Picotti lab at the IMSB at ETH Zürich

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Picotti Lab reposted

vivireber.bsky.social
@vivireber.bsky.social

Out now: ATP-competitive inhibitors lock kinases in a pseudo-active conformation and modulate their non-catalytic functions. We show that these on-target, off-machanism effects can cause unexpected phenotypes and how to screen for these effects. Read more at link.springer.com/article/10.1...

link.springer.comParadoxical non-catalytic kinase functions are driven by inhibitor-induced displacement of autoinhibitory domains - Molecular Systems BiologyATP-competitive kinase inhibitors represent one of the largest classes of targeted anti-cancer drugs. While their primary mechanism is to block catalytic activity, they can also trigger paradoxical ph...
Picotti Lab
@picottilab.bsky.social

In mass spectrometry-based proteomics, peptides can fragment after chromatographic separation and before MS analysis. This phenomenon is called in-source fragmentation (ISF), and the resulting fragment peptides can be misinterpreted as biologically meaningful.

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Picotti Lab
@picottilab.bsky.social

Our findings highlight the importance of detecting in-source fragments as part of standard data analysis workflows to avoid misinterpretation. With increasingly sensitive mass spectrometers detecting ever more m/z features, ISF is likely to become a growing concern.

Picotti Lab
@picottilab.bsky.social

In mass spectrometry-based proteomics, peptides can fragment after chromatographic separation and before MS analysis. This phenomenon is called in-source fragmentation (ISF), and the resulting fragment peptides can be misinterpreted as biologically meaningful.

Picotti Lab
@picottilab.bsky.social

In our latest study, we assessed the prevalence and impact of ISF on protein- and peptide-centric proteomics approaches, including immunopeptidomics, phosphoproteomics, and structural proteomics. Our analysis covered 38 datasets, both newly generated and previously published.

Picotti Lab
@picottilab.bsky.social

The extent of ISF varied substantially between datasets, influenced by factors such as sample complexity, instrumentation, peptide sequence, and method parameters. In some cases, ISF accounted for more than 30% of peptide identifications.

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Picotti Lab
@picottilab.bsky.social

Our study supports the notion that structural differences between alpha-synuclein fibrils play a role in the differences between PD, DLB and MSA. Also, differential interaction with the ubiquitin-proteasomal system may explain differential fibril accumulation in these diseases.

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Picotti Lab
@picottilab.bsky.social

Next, we saw that each disease strain of alpha-synuclein fibrils had different sets of cellular proteins as potential interactors, including several associated with protein turnover.

Picotti Lab
@picottilab.bsky.social

Finally, we monitored the cellular consequences of alpha-synuclein uptake. We again found strain-specific hits and validated a few of them using CRISPR-based overexpression with Adriano Aguzzi @UZH. These included three E3 ligases, which may be interesting potential drug targets for follow up work.

Picotti Lab
@picottilab.bsky.social

We studied the structural and cellular mechanisms of three synucleinopathies – Parkinson’s disease, Dementia with Lewy Bodies and Multiple Systems Atrophy. DOI: 10.1038/s44320-026-00199-5

Picotti Lab
@picottilab.bsky.social

In our three-part study, we first found that alpha-synuclein fibrils amplified from PD, DLB and MSA patient samples had different structures. This was true in vitro, within cell lysates, and within patient brain homogenates.

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Picotti Lab
@picottilab.bsky.social

We profiled structural dynamics of hundreds of proteins from biomolecular condensates in stressed human cells, monitored structural changes in #RNA-binding sites and #intrinsically-disordered regions, and showed that we can identify a known #drug-target interaction, all inside of live cells.

Picotti Lab
@picottilab.bsky.social

We've developed in-cell LiP-MS to identify protein structural changes in live cells proteome-wide It captures changes in labile structures, like #biomolecular condensates

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