Fletcher Lab

We’re thrilled to onboard Alice Wicks @ubch-alice.bsky.social in the lab this week. Alice trained with Danny Huang @cruk-si.bsky.social and has developed exciting new ideas for co-opting E3s for targeted degradation. Welcome to the team, Alice.

We’ve made some new tools to manipulate N-recognins. Check them out in our preprint.
www.biorxiv.org/content/10.1...

Join @uofglasgow.bsky.social for a funded 3.5 year PhD programme:

www.gla.ac.uk/colleges/mvl...

Also up for grabs is a project on antiviral PROTACs, supervised by us and the France lab (School of Chemistry) should ubiquitin and viruses appeal! Please get in touch with any questions.

Excited to share the peer-reviewed version of our work, now online in @embojournal.org! Big thanks to our reviewers and @hvodermaier.bsky.social for facilitating this process. Looking forward to continuing this fun collaboration with @michaelnadbio.bsky.social!
www.embopress.org/doi/full/10....

A #postdoc position in atypical #ubiquitin signalling and protein binder engineering is opening soon in my lab at DTU Bioengineering! Get in touch if you are interested.

🎉 Fletcher lab PhD student Emma Davies reflecting on her prize winning talk - we’re super proud of you Emma - many congrats! 🎉

@cvrinfo.bsky.social @uofgsii.bsky.social @uofgmvls.bsky.social

Illustration depicting a bacterium under assault by phage. The bacterium “sees” phage immune evasion proteins and protects itself using a newly described antiphage system called Panoptes, named for the many-eyed mythical giant Argus Panoptes. Credit: Clair Huffine Insight Illustrations LLC

Our work on the Panoptes antiphage system is published! Here we find that Panoptes "watches" the cytosol for phage immune evasion proteins–captured in this illustration by Clair Huffine of Insight Illustrations. A beautiful example of the effector triggered immunity paradigm.

Viro3D: a comprehensive database of virus protein structure predictions | Molecular Systems Biology imageimageViro3D provides proteome-level, high confidence AI-protein structure predictions for >4,400 viruses, allowing mapping of form and function across the human and animal virosphere. Viro3D i...

Viro3D paper is out! We predicted 85,000 protein structures from human & animal viruses. 1/5 🧵

📑 Paper doi.org/10.1038/s443...
🔭 Explore virosphere viro3d.cvr.gla.ac.uk

A Leishmania virulence factor harnesses an allosteric kinase switch to regulate its ubiquitin ligase activity Stringent control of ubiquitylation is a central requirement of signaling specificity in eukaryotes. Here, we discover a domain module integrating pro…

Allosteric activation of a ubiquitin ligase by an internal kinase domain! Congratulations to our team member Thornton Fokkens for this fascinating discovery in a neglected disease area with strong therapeutic need. Many thanks to all our great collaborators!
www.sciencedirect.com/science/arti...

Aye

Liam please can we come to you for advice when naming our manuscripts?

An AI for an AI: identifying zoonotic potential of avian influenza viruses via genomic machine learning Avian influenza remains a serious risk to human health via zoonotic transmission, as well as a feasible pandemic threat. Although limited zoonotic cases have resulted from the current epizootic outbre...

🚨📝 New work via @thepandemicinst.bsky.social now preprinted!

We took ~19000 sequences of avian influenza virus and trained machine learning models on >40000 genomic/proteomic features - the resulting ensemble can predict zoonotic potential with AUC=0.95. More below!

www.biorxiv.org/content/10.1...

A few months ago, our review “The Molecular Toolbox for Linkage Type-Specific Analysis of Ubiquitin Signaling” 🧬🧰🛠️ came out in ChemBioChem. Time to give it a spotlight!

chemistry-europe.onlinelibrary.wiley.com/doi/full/10....

Had a brilliant time at the 9th International Calicivirus Conference in Banff (www.calicivirusconference.com) - phenomenal science in a phenomenal setting! It was great to present my PhD work so far (thanks @dbhella.bsky.social for the pic). Here's to many more!

ZNFX1 uses two-component ubiquitin circuitry to quarantine viral RNA The detection of viral RNA inside cells triggers a diverse range of antiviral responses, including global translation inhibition, interferon secretion and RNA sequestration. Mutations in the gene ZNFX...

Pre-print: our description of RZ affiliate ZNFX1 is now online.

On binding viral RNA, ZNFX1 generates parallel Ub currents, coordinating Ub-dependent RNA silencing and aggregate resolution.

Huge effort from first authors Dan Squair and @eilidhrivers.bsky.social

www.biorxiv.org/content/10.1...

So excited to see our newest study out in print! Led by the brilliant @jgezelle.bsky.social and @sophiekorn.bsky.social, we discovered how viruses from highly divergent families converge on a shared RNA structure mechanism to inhibit cellular nucleases. #RNAsky #LoveVirology

Glad to share the final version of our story about the UBR4 complex, an E4 ligase protein quality control hub @science.org. Now with more cryo-EM structures and a deeper dive into substrate recognition, especially escaped mitochondrial proteins @clausenlab.bsky.social www.science.org/doi/10.1126/...

A split-site E3 ligase mechanism enables ZNFX1 to ubiquitinate and cluster single-stranded RNA into ubiquitin-coated nucleoprotein particles Grabarczyk et al. show the structure and mechanism of a non-canonical ubiquitin ligase, which is activated through nucleic-acid-induced oligomerization and is critical for cell survival during immune ...

Happy to share our work on the structure and function of the unusual E3 ligase ZNFX1 @cp-cell.bsky.social. It uses a nucleic acid-activated transthiolation mechanism, ubiquitinating and clustering RNA to protect cells in an immune response. @clausenlab.bsky.social
www.cell.com/cell/fulltex...

Opening for a biochemist to help us in the characterisation of novel ubiquitin-based antivirals. Diverse backgrounds welcomed; a keen sense of adventure is a must 😁

Details and criteria are below; please get in touch with any questions.

www.jobs.gla.ac.uk/job/research...

Post 5/5 🧵
IMPACT: This transforms tick-borne disease research:
🎯 New drug targets
🎯 Understanding vector competence
🎯 Virus-tick evolution
Testing if mechanisms work across other tick viruses next.

👨‍🔬 collaborative project with @alf-castello.bsky.social and @alainkohlvirology.bsky.social

Identification of RNF114 as ADPr-Ub reader through non-hydrolysable ubiquitinated ADP-ribose - Nature Communications Deltex E3s modify ADP-ribosylated targets with ubiquitin, creating a hybrid modification whose readers remains unknown. Here, the authors synthesise a non-hydrolysable probe that mimics the modificati...

A few years back we discovered a dual hybrid protein modification composed of ADP-ribose dinucleotide and ubiquitin (ADPr-Ub). Now we reveal that ADPr-Ub can be further ubiquitinated by the E3 ubiquitin ligase RNF114!
www.nature.com/articles/s41...

www.science.org/doi/10.1126/...

Nine rounds of directed evolution resulted in LcαE7 variants with increased rates of OP-hydrolysis. Three LcαE7 genes (wild-type, G137D and R9) were introduced into the genome of Drosophila. Fluorometric substrate DEUP, and insecticides Diazinon and Paraoxon are shown with the scissile bond indicated in red.

How predictable are the evolutionary pathways leading to insecticide resistance? Why do some species gain resistance while others do not? We explore these questions in our latest preprint. A huge effort from Rebecca Frkic, Alex Giang, Colin Jackson and the team.

www.biorxiv.org/content/10.1...

PhD student in Biochemistry - Uppsala University PhD student in Biochemistry, Disciplinary Domain of Science and Technology, Faculty of Chemistry, Department of Chemistry - BMC, Uppsala University

We are looking for a PhD student in (mostly )wet-lab biochemistry to work on short linear motifs, intrinsically disordered regions, in the context of the Marie Curie network "IDPro". More info an apply here: www.uu.se/en/about-uu/...

postdoc opening in vienna: study lipid droplets (LDs) with integrative structural biology, uncover how LD proteins shuttle between cytosol & nucleus to regulate lipid metabolism, organelle architecture and immune response. #VIP3 #lipidtime #cryoEM #coffee training.vbc.ac.at/post-docs/vi...

🚨🚨 News from the @castello-lab.bsky.social and @shabazlab.bsky.social. Our work, led by Louisa Iselin, reveals pervasive changes in the RNA-bound proteome induced by interferon. #RNA, #immunity, #interferon, #host-virus www.biorxiv.org/content/10.1...

Multi-omics analysis of SFTS virus infection in Rhipicephalus microplus cells reveals antiviral tick factors - Nature Communications Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV) is a deadly tick-borne virus and a growing global health threat. In this study, Petit et al. used a multi-omics approach on SFTSV-infected tic...

OMG! I can finally share my joy to see my SFTSV work published in @natcomms.nature.com! This adventure started by the award of my MSCA grant and my move to the Kohl and @brennanlab.bsky.social at @cvrinfo.bsky.social. Let's chat about how we discovered novel tick anti-viral effectors!

Happy that my work on RNF213 has been published as a part of doi.org/10.1038/s414...!

Many thanks to all the groups involved:
@clausenlab.bsky.social
@e3chembio.bsky.social
@fletcherlab.bsky.social

Have a look at the summary from Fletcher lab for an insider perspective of the paper's history:

A family of E3 ligases extend K11 polyubiquitin on sites of MARUbylation Ubiquitin (Ub) cooperation with other post-translational modifications provides a tiered opportunity for protein regulation. Small modifications to Ub such as phosphorylation, acetylation, or ADP-ribo...

Sharing the next installment of our fun collaboration with @michaelnadbio.bsky.social at the interface of #ubiquitin and #ADP-ribosylation! Building upon our identification of cellular MARUbylation, we now identify reader/writer E3 ligases that extend K11 polyUb! 🧵
www.biorxiv.org/content/10.1...

Excited to share our new paper on Nature - how Ku accommodates Alu expansion in primates by binding to dsRNA, providing a clue for both the high levels of Ku and its essentiality in human cells. Thank @chaolinzhang @hchung03 @LenaSteckelberg More to come www.nature.com/articles/s41...

Thanks to all the many who contributed along the way and the very supportive editorial team @natcomms.nature.com

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