Craig M. Crews

Check out the highlight! Great work by our lab neighbours @hemmo-lab.bsky.social @unidue-zmb.bsky.social @unidue.bsky.social

A proteome-wide dependency map of protein interaction motifs Nature Structural & Molecular Biology, Published online: 06 March 2026; doi:10.1038/s41594-026-01762-2Ambjørn and Meeusen et al. functionally characterize all reported and a comprehensive set of predicted short linear motifs (SLiMs) using base-editing screens, identifying 450 reported and 264 predicted SLiMs required for normal cell proliferation.

ICYMI: New online: A proteome-wide dependency map of protein interaction motifs

A SLiM view of the human proteome Nature Structural & Molecular Biology, Published online: 06 March 2026; doi:10.1038/s41594-026-01770-2Many protein–protein interactions are mediated by compact amino acid stretches known as short linear motifs (SLiMs) that lack a stable tertiary structure. A study now uses high-throughput precision genome editing to decode the function of over 7,000 SLiMs across the human proteome, providing insights into their roles in cellular homeostasis.

ICYMI: New online: A SLiM view of the human proteome

Quantitative Degradation Rate Assessment of bioPROTACs Based on Peptide Degrons, E3 Domains, Adapters and Conjugated Small Molecules Protein-based bispecific degraders, known as bioPROTACs, have emerged as powerful tools for targeted protein degradation through the ubiquitin-proteasome system (UPS). However, the relative efficacy of various recruitment domains within these degraders remains poorly understood. To address this knowledge gap, we conducted a comprehensive comparison of recruitment domains in bioPROTACs, utilizing eGFP as a proof-of-principle degradation target and an eGFP-binding DARPin with known structure as an adapter. Our innovative approach combined microinjection and live-cell microscopy, enabling a detailed assessment of directly measured degradation rates as a single-cell kinetic readout, unaffected by uptake or biosynthesis rates of the degrader, and across the different chemical classes. We examined nine degron peptides, three E3 ligase domains or adapters, and two series of small-molecule binders, linked in various geometries. Our results revealed that bioPROTACs based on E3 or adapter protein domains and small molecules generally exhibited the highest degradation rates, while most degron peptides showed comparatively low efficacy. Notably, for VHL-ligand-1 and thalidomide, the placement of the coupling site and linker position significantly influenced performance. This study provides crucial insights into the design and optimization of bioPROTACs, paving the way for the development of more effective degraders for specific applications. Our findings contribute to the growing field of targeted protein degradation and offer valuable guidance for researchers seeking to enhance the efficacy of bioPROTAC-based therapeutic approaches.

pubs.acs.org/doi/10.1021/...

Degrons and degradation signals beyond short linear motifs - Nature Chemical Biology Degrons are degradation signals in target proteins to direct recognition and degradation by the ubiquitin–proteasome system. Wang et al. introduce degrons of different types, with an emphasis on high-...

www.nature.com/articles/s41...

Terraforming the KRAS lipid landscape - Nature Chemical Biology ELOVL6 is an acyltransferase involved in the synthesis of saturated and monounsaturated fatty acids. New work finds that inhibition of ELOVL6 function results in mislocalization of oncogenic KRAS from...

www.nature.com/articles/s41...

Intrinsically disordered domains expand the CAR T cell toolbox - Nature Chemical Biology A study establishes intrinsically disordered regions (IDRs) as a new module in chimeric antigen receptor (CAR) engineering. The intrinsic biophysics of IDRs — transient, multivalent interactions — can...

www.nature.com/articles/s41...

Image of FAF2's predicted helical domain interacting with the UFD1 UT3 domain. Next to this are similar images showing the predicted binding of de novo designed protein binders to the same region. Above is a sequence alignment indicating the key residues involved in the interaction.

🚨⚠️ New Preprint Alert! ⚠️ 🚨
www.biorxiv.org/content/10.6...

Screening p97 cofactors, @prithadg.bsky.social identified FAF2 as the strongest activator of the p97-UFD1-NPL4 complex. Leveraging her mechanistic descoveries, we designed 𝘥𝘦 𝘯𝘰𝘷𝘰 binders that could also enhance p97 substrate unfolding.

An overview of #LipidMetabolism in #Homeostasis & disease, highlighting how lipid signaling reprograms #ImmuneCells and exploring innovative therapeutic strategies for #Cancer, #CardiovascularDisease, and metabolic disorders.

#OpenAccess: doi.org/10.1038/s413...

De novo design of potent CRISPR–Cas13 inhibitors | Nature Chemical Biology CRISPR–Cas systems are transformative tools for gene editing that can be tuned or controlled by anti-CRISPRs (Acrs)—phage-derived inhibitors that regulate CRISPR–Cas activity. However, Acrs that can inhibit biotechnologically relevant CRISPR systems are relatively rare and challenging to discover. To overcome this limitation, we describe a highly successful and rapid approach that leverages de novo protein design to develop new-to-nature proteins for controlling CRISPR–Cas activity. Here, using Leptotrichia buccalis CRISPR–Cas13a as a representative example, we demonstrate that Acrs designed using artificial intelligence (AIcrs) are capable of highly potent and specific inhibition of CRISPR–Cas13a nuclease activity. We present a comprehensive workflow for design validation and demonstrate AIcr functionality in controlling CRISPR–Cas13 activity in bacterial and human cells. The ability to design bespoke inhibitors of Cas effectors will contribute to the ongoing development of CRISPR–Cas

Check out Nature Chem Biology's latest: De novo protein design crafts potent CRISPR-Cas13 inhibitors. Game-changer for gene editing! PMID:41588195, Nat Chem Biol 2026, @nchembio @OTSociety @NAR_Open https://doi.org/10.1038/s41589-025-02136-3 #Medsky #Pharmsky #RNA #ASHG #ESHG 🧪

We made FLIP2, a protein fitness benchmark spanning seven new datasets, including enzymes, protein-protein interactions, and light-sensitive proteins, as well as splits that measure generalization relevant to real-world protein engineering campaigns.

This project started with confusion 🤔 www.nature.com/articles/s41...

Loss of LUBAC or OTULIN causes severe inflammatory disease. But patients also show clear metabolic defects.

Neither LUBAC nor OTULIN had been linked to metabolic regulation.

So where do these metabolic manifestations come from?

How an exercise-activated enzyme helps to keep the brain young A protein reinforces the blood–brain barrier, which becomes leaky with age.

Exercise prevents brain ageing and memory loss by strengthening the blood–brain barrier

go.nature.com/4kVU2hy

Actin N-terminal maturation can be blocked by a butynamide stereoprobe which acts as an ACTMAP inhibitor. Preprint by Xiong et al. Benjamin Cravatt and Bruno Melillo. @ispt-proteinterm.bsky.social
www.biorxiv.org/content/10.6...

And a new paper from the lab. A follow up to a previous study in which we elucidate the mechanism of the nuclear transport. Read the full story: www.nature.com/articles/s41...

Lipids challenge ligands to control receptors

The behaviour of a receptor protein can be influenced by the presence of certain lipids in the membrane it is embedded in.

🔗 buff.ly/G1Zl6cZ

The role of KRAB zinc-finger proteins in expanding the domestication potential of transposable elements

#CLL cells accumulate lipid peroxides & iron, predisposing them to #ferroptosis; #BTK inhibition raises #TFRC and sensitizes cells, while combining #ibrutinib with #GPX4 blockade enhances efficacy, with TFRC and #ACSL1 emerging as targets.

#OpenAccess #STTT: doi.org/10.1038/s413...

Spending lots of time to modify same PDB and finally I could make image with ligting molecule.

Structural ontogeny of protein-protein interactions: www.science.org/doi/10.1126/...

Fundamental work on how PPIs (co)evolve, combining directed evolution and machine learning to reveal the role of chance and contingency.

Fantastic teamwork by Irene Schwartz & Valentina Budroni from the lab of @versteegga.bsky.social @maxperutzlabs.ac.at together with colleagues in our SFB consortium & beyond 👏Great to see the story out @natcomms.nature.com
🔗 www.nature.com/articles/s41...

SAVE THE DATE: Ubiquitin & Friends Symposium 2026 on April 29-30 or even better, sign up now: lnkd.in/eEQmaCYT
It takes place at Van Swieten Hall, 1090 Vienna & is organized by the SFB Targeted Protein Degradation (incl. numerous research groups at Vienna BioCenter)
@sfb-tpd-vienna.bsky.social

Ancient co-option of LTR retrotransposons as yeast centromeres - Nature Evolutionarily related ‘proto-point’ centromeres providing resolution to the evolutionary origins of point centromeres are identified in yeast, and comparison shows they evolved in an ancestor with re...

Our paper is now out in Nature:

“Ancient co-option of LTR retrotransposons as yeast centromeres”

www.nature.com/articles/s41...

A short thread on how retrotransposons helped give rise to yeast point centromeres.

1/14

A model to describe what we show in the paper. INVs are important for sequestering GLUT4 and related proteins into GSVs, the vesicles that are mobilised in response to insulin.

🚨 We have a new preprint out! 🧪

In this paper we look at GLUT4 trafficking. This is a short explainer thread, but please read the paper!

1/n 🧵

www.biorxiv.org/content/10.6...

Papers are like buses... You wait for ages, then two come along at once.

Huge congrats to @bornanovak.bsky.social and @jefflotthammer.bsky.social for pushing and driving every aspect of this work, preprinted ~1 year ago to the day (Friday before BPS), now published!

www.nature.com/articles/s41...

Our paper is out in @natcomms.nature.com! APOBEC3s drive mutagenesis in cancer. We uncover a novel pathway keeping them in check. The key is APOBEC3 binding of cellular RNAs, which simultaneously controls their nuclear localization and shields them from degradation.

Read it here: rdcu.be/e4qaa

Such a pleasure to share our commentary on #UFMylation client diversity published in @natrevmcb.nature.com. Thanks to @lisaheinke.bsky.social for the opportunity to write it, reviewers for their peer review contribution, and members of our lab for discussions.
Link: www.nature.com/articles/s41...

Engineering intrinsically disordered regions for guiding genome navigation Liu et al. design and test synthetic IDRs based on simple design rules derived from mutation-based analysis of 25 native TF IDRs. They show that hydrophobic amino acids endow activity, acidic ones pre...

Engineering intrinsically disordered regions for guiding genome navigation: Molecular Cell www.cell.com/molecular-ce...

A Chemical Proteomics Method to Quantify Cysteine S-Acylation S-acylation, often referred to as S-palmitoylation, is a reversible and dynamic posttranslational modification that corresponds to the addition of a long-chain fatty acid to cysteine (Cys) residues. Established mass spectrometry-based chemoproteomics methods have improved our understanding of the S-acylation proteome, notably by identifying hundreds of S-acylated proteins, sometimes with the modified Cys. However, the precise quantification of S-acylation levels for each Cys within a single sample remains challenging at the proteome level. Quantification of S-acylation levels is critical to further our understanding of protein S-acylation in cellular function and its role in health and diseases. We report here the development of an S-acylation quantification workflow based on the sequential labeling of free Cys and S-acylated Cys with isotopic labeling reagents. The workflow was extensively optimized, notably by comparing the number of sites identified with two alkyne-tagged Cys-reactive isotopic probes and four azido-tagged biotin-based capture reagents. By integrating this enhanced workflow with high-field asymmetric waveform ion mobility spectrometry (FAIMS) on LC–MS/MS instruments for the separation of labeled peptides, over 17,000 unique Cys could be quantified in biological samples. Application of the S-acylation quantification workflow to cellular proteomes allowed for the quantification of S-acylation levels in a HeLa proteome. We also identified dynamic S-acylation changes in response to autophagy induction.

A Chemical Proteomics Method to Quantify Cysteine S-Acylation | ACS Chemical Biology pubs.acs.org/doi/abs/10.1...

#chembio and #bioorganic crowd: Registration to ESBOC is open. Join us on 27th-29th May for the oldest meeting in chemical biology in Europe, at the awesome Schlosshotel Pillnitz in Dresden!

Check out www.esboc.org.uk or register directly at eveeno.com/esboc2026!