Malte Gersch

Recurrent acquisition of nuclease-protease pairs in antiviral immunity Antiviral immune systems diversify by integrating new genes into existing pathways, creating new mechanisms of viral resistance. We identified genes encoding a predicted nuclease paired with a trypsin...

Our nuclease-protease story is out! We explored a fascinating case of coevolution and modularity in prokaryotic immune systems: www.science.org/doi/10.1126/...

Thanks to wonderful coauthors/collaborators/friends, the whole @doudna-lab.bsky.social and everyone at @innovativegenomics.bsky.social

From Pharmacophore to Warhead: NAD+‐Targeting Triazoles as Mechanism‐Based Sirtuin Inhibitors We report “Sirtuin Trapping Ligands” (SirTraps), mechanism-based 1,2,3-triazole inhibitors that hijack sirtuin (SIRT) catalysis to form covalent triazolium– or triazole–ADP-ribose (ADPR) adducts from...

We call these mechanism based sirtuin inhibitors SirTraps that trap the enzyme via this ADP ribose adduct onlinelibrary.wiley.com/doi/10.1002/... 2/

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.

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....

ADPr gets a ubiquitin upgrade - Nature Chemical Biology MARUbylation is a hybrid post-translational protein modification in which mono-ADP-ribosylation acts as a scaffold for sequential mono- and polyubiquitylation. Recent studies illuminate its substrates...

Also enjoyed reading the News & Views from @maltegersch.bsky.social, which beautifully summarizes the recent advancements in studying MARUbylation as a novel hybrid PTM.
www.nature.com/articles/s41...

Enteropathogenic bacteria evade ROCK-driven epithelial cell extrusion - Nature The bacterial ubiquitin ligase NleL evades host defence mechanisms both by inhibiting pyroptosis and by preventing infected intestinal epithelial cells from being extruded into the lumen and expelled ...

Check out our new publication, a collaboration with Giovanni Luchetti and Vishva Dixit @ Genentech.
We show that the E.coli effector NleL inhibits intestinal epithelial cell extrusion after #inflammasome activation via degrading the kinases ROCK1 and 2!!
www.nature.com/articles/s41...

Explainer 1/8

Hijacking a bacterial ABC transporter for genetic code expansion - Nature Bacterial ATP-binding cassette (ABC) transporters can be utilized and engineered to transport non-canonical amino acids into Escherichia coli for highly efficient synthesis of proteins with novel func...

🚨Our paper is out! 🥳
Hijacking a bacterial ABC transporter for efficient genetic code expansion.
Many congrats to everyone involved - a multi-year effort led by @taruniype.bsky.social @maxfottner.bsky.social
www.nature.com/articles/s41...

it all started years ago with a failed experiment
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This looks very useful (as does the preprint from the Hummer lab). I‘d be curios in how many of those examples one would expect a precisely positioned Ub based on nearby UBDs?

You’ve heard of ubiquitination, meet deazaguanylation: Doug Wassarman in our lab discovered phage defense pathways have co-opted Q nucleobase biosynthetic enzymes to catalyze a new form of protein conjugation chemistry @science.org

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

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...

Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations Mitochondrial synthesis of adenosine triphosphate is essential for eukaryotic life but is dependent on the cooperation of two genomes: nuclear and mitochondrial DNA (mtDNA). mtDNA mutates ~15 times as...

How can mitophagy be an effective quality control mechanism if mtDNA mutations reach high enough levels to cause disease?

This question led us into a dark path, full of concepts of evolutionary genetics, germline stem cell biology and mito-nuclear compatibility.

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

Just out in @science.org: Together with the lab of @wilhelmpalm.bsky.social, we used sequential in-vitro/in-vivo CRISPR screens to decipher metabolic adaptations in tumors. We find that acidosis is a dominant factor that shapes energy metabolism and stress resilience. www.science.org/doi/10.1126/...

The functional landscape of the human ubiquitinome Protein ubiquitination regulates cell biology through diverse avenues, from quality control-linked protein degradation to signaling functions such as modulating protein-protein interactions and enzyme...

new preprint: Ubiquitin is a protein modification linked with degradation but known to regulate other functions. Over 100k ubiquitination sites have been discovered and here we (@julianvangerwen.bsky.social + others) try to prioritize those most critical to the cell www.biorxiv.org/content/10.1...

Recommendations for Quantitative Data-Independent Acquisition (DIA) Proteomics using Controlled Quantitative Experiments (CQEs) Advances in mass spectrometry and associated computational tools have resulted in the wide-spread adoption of Data-Independent Acquisition (DIA) for proteomics. Experiments using state-of-the-art inst...

Are you using DIA mass spectrometry in proteomics?

We have just put this paper online: www.biorxiv.org/content/10.1...

Here, we came up with some Recommendations for Quantitative Data-Independent Acquisition (DIA) Proteomics using Controlled Quantitative Experiments (CQEs)

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Highly specific intracellular ubiquitination of a small molecule - Nature Chemical Biology Li et al. discovered that the cytotoxic synthetic small molecule BRD1732 is directly ubiquitinated in cells. Ubiquitination of BRD1732 is E3 ligase dependent and leads to inhibition of proteasomal deg...

A new paper reports direct ubiquitination of a small molecule BRD1732 in cells. BR31732 ubiquitination is E3 ligase-dependent and leads to inhibition of proteasomal degradation.

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

Origins of life: the molecules that could have unlocked peptide synthesis For life to emerge on Earth, peptides must first have formed without the aid of enzymes — but how? Reactions of sulfur-containing molecules might have been key.

For life to emerge on Earth, peptides must first have formed without the aid of enzymes — but how? Reactions of sulfur-containing molecules might have been key

go.nature.com/4oX04jC

Selective ubiquitination of drug-like small molecules by the ubiquitin ligase HUWE1 Nature Communications - Ubiquitination is a versatile modification system in eukaryotic cells. Here, the authors unveil that the ubiquitin ligase HUWE1 can modify drug-like small-molecule...

Delighted to share our work on cellular ubiquitination of drug-like compounds by HUWE1 - a surprising journey! Kudos to all contributors & first authors, Barbara Orth and Pavel Pohl. Sincere thanks to @ireserra.bsky.social ‬ #NatCommun for expertly guiding the winding publishing path.
rdcu.be/eDzPk

Fully‐Functionalized Natural Product Probes to Expand the Chemical Tractability of the Human Proteome onlinelibrary.wiley....

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#proteomics #prot-paper

This one is a bit of a departure from the usual and definitely a work in progress!

We found that by using ab initio reconstruction at very high res, in very small steps, we could crack some small structures that had eluded us - e.g. 39kDa iPKAc (EMPIAR-10252), below.

Read on for details... 1/x

The BUB1 and BUBR1 paralogs scaffold the kinetochore fibrous corona The kinetochore fibrous corona docks on CENP-E and a second elusive receptor identified as the checkpoint protein BUB1.

The BUB1 and BUBR1 paralogs scaffold the kinetochore fibrous corona | Science Advances www.science.org/doi/10.1126/...

Congratulations @vcmentowski.bsky.social for solving a remarkably challenging molecular puzzle

Covariation MS uncovers a protein that controls cysteine catabolism - Nature A mass spectrometry-based approach globally identifies protein regulators of metabolism and reveals the role of LRRC58 in controlling cysteine catabolism.

Covariation MS uncovers a protein that controls cysteine catabolism

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

Beautiful work from Ed Chouchani!

Targeted DNA ADP-ribosylation triggers templated repair in bacteria and base mutagenesis in eukaryotes - Nature Biotechnology Append editing of ADP-ribosyl to thymine is used for precise modifications in bacteria and eukaryotes.

Targeted DNA ADP-ribosylation triggers templated repair in bacteria and base mutagenesis in eukaryotes - @helmholtz-hiri.bsky.social go.nature.com/4n7zDpG

New paper alert! Stellar work by brilliant lead first author @annaleder.bsky.social together with project leader @masgu.bsky.social reveals a groundbreaking discovery: PDIA6 forms multi-chaperone condensates creating "folding factories" in the ER. www.nature.com/articles/s41...

ZBTB11 depletion targets metabolic vulnerabilities in KRAS inhibitor-resistant PDAC - Nature Chemical Biology Depletion of a transcriptional factor ZBTB11 using molecular glue degraders can overcome oxidative-phosphorylation-mediated KRAS inhibitor resistance in pancreatic ductal adenocarcinoma with low acute...

Excited to share our latest work developing molecular glue degraders of ZBTB11, now out in @natchembio.nature.com
www.nature.com/articles/s41...

Engineered reactivity of a bacterial E1-like enzyme enables ATP-driven modification of protein and peptide C termini Nature Chemistry - In living systems, ATP provides an energetic driving force for protein synthesis and modification. Now, an engineered enzymatic tool has been developed for high-yield, ATP-driven...

Excited to share our latest: we engineered the reactivity of a bacterial E1-like enzyme for ATP-driven modification of C termini. Our tool mimics the logic of peptide bond formation in biology for precision modification of proteins in vitro. 🧪https://rdcu.be/ewN7C

SuFEx-based antitubercular compound irreversibly inhibits Pks13 - Nature A preclinical covalent compound, CMX410, contains a aryl fluorosulfate warhead that targets the acyltransferase domain of Mtb Pks13, an essential enzyme in cell-wall biosynthesis, making it a pro...

This has a neat mechanism of inhibition:
www.nature.com/articles/s41...

This illustration shows consecutive stages during operation of a molecular catenating machine.

This week in Science, researchers report an artificial molecular motor that can twist a molecular thread to form a mechanically interlocked molecule. The approach creates opportunities to fabricate mechanically interlocked molecules with precise structural control.

Learn more: scim.ag/40FboGP

Thrilled to share our work on the role of Ataxin-3 in lysosome regeneration published in @embojournal.org . Here we show that Atxn3 targets K48-K63 branched ubiquitin chains on damaged lysosomes and mediates restoration of lysosomal function via microautophagy.

www.embopress.org/doi/full/10....

Lipoyl deglutarylation by ABHD11 regulates mitochondrial and T cell metabolism Nature Chemical Biology - Glutarate rewires cell metabolism through conjugation to proteins or fatty acids, but how glutarylation is regulated is unclear. ABHD11 was identified as a...

Delighted to share our latest work on ABHD11 as a novel deglutarylating enzyme, and its role in T cell metabolism @natchembio.nature.com rdcu.be/ewiYZ. Many congratulations to co-first authors Guine Grice, Eleanor Minogue and @hudsonwilco.bsky.social! Great team effort with Randall Johnson's lab.

Very happy to see our contribution to a better understanding of Hsp70/90 #chaperones online! Congrats and a big thank you to all co-authors, collaborators and reviewers! #proteostasis @poepsel-lab.bsky.social @crc1430.bsky.social @unidue-zmb.bsky.social