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Articles by Malte Gersch
ZnF-UBP domains regulate deubiquitinase activity by relieving ubiquitin product inhibition
Abstract Most ubiquitin specific protease (USP) deubiquitinases (DUBs) combine non-selective catalytic domains with one or multiple ‘exo’-domains that contribute substrate specificity and localisation, but are generally poorly characterised. Zinc-Finger UBP (ZnF-UBP) domains exist in 12 USP DUBs, yet their function is unclear. We here comprehensively analyse human ZnF-UBP domains, and reveal that 8 of 14 bind ubiquitin (Ub) via an unattached Ub C-terminal GlyGly motif.
Targeted degradation of USP7 in solid cancer cells reveals distinct effects of deubiquitinase degraders and inhibitors
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Abstract Proteolysis-targeting chimeras (PROTACs) co-op the ubiquitin system for targeted protein degradation, creating opportunities to interrogate cellular functions of proteins through “chemical knockdown”. However, matched pairs of protein degraders and inhibitors, that possess high specificity and chemical complementarity, for individual components of the ubiquitin system have remained scarce. This includes reagents to modulate activity and abundance of deubiquitinases (DUBs).
By Nikolas Klink, Sebastian Urban, Johanna A. Seier, Bikash Adhikari, Martin P. Schwalm, Juliane Müller, Madeleine Dorsch, Jennifer Jung, Markus Vogt, Farnusch Kaschani, Johannes Koch Verified, Siska Führer, Markus Kaiser, Nina Schulze, Stefan Knapp, Elmar Wolf, Annette Paschen, Barbara M. Grüner, Malte Gersch, Philine Steinbach
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Nature
Verified
Monovalent pseudo-natural products supercharge degradation of IDO1 by its native E3 KLHDC3 - Nature Chemistry
Abstract Targeted protein degradation modulates protein function beyond the inhibition of enzyme activity or protein–protein interactions. Most degrader drugs function by directly mediating the proximity between a neosubstrate and a hijacked E3 ligase. Here we identify pseudo-natural products derived from (−)-myrtanol, termed iDegs, that inhibit and induce degradation of the immunomodulatory enzyme indoleamine-2,3-dioxygenase 1 (IDO1) by a distinct mechanism.
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, molecular recognition, and emerging roles in DNA repair.
Distinct USP25 and USP28 Oligomerization States Regulate Deubiquitinating Activity
Highlights • Insertions in USP25 and USP28 catalytic domains mediate their oligomerization • DUB activity of USP25, but not USP28, is inhibited by tetramerization • An autoinhibitory motif in USP25 blocks Ub binding, impairing its activity • Dimers of USP28, as well as dimers and tetramers of USP25, exist in cells Summary The evolutionarily related deubiquitinating enzymes (DUBs) USP25 and USP28 comprise an identical overall domain architecture but are functionally non-redundant: USP28...
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