Since the 1950s, long before the discovery of the ubiquitin-proteasome system, Tryptophan 2,3-dioxygenase (TDO2) emerged as a model for protein stability – a mystery now solved!
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Excited to share our latest study on how K29/K48-branched #ubiquitin chains are forged by the #E3 ligase TRIP12, and how this suggests a consensus mechanism for chain formation by HECT E3s!
@natsmb.nature.com
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www.nature.com/articles/s41...
Occupation of an enzyme exosite to regulate accessability of a phosphodegron to a kinase-E3 ligase cascade is a new mechanism of metabolite-gated protein degradation.
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Using biochemistry, chemical biology, and cryo-EM, Maiwald et al. elucidate how TRIP12 forms K29 linkages and K29/K48-linked branched ubiquitin chains, revealing a mechanism for polyubiquitylation sha...
SAR studies with Trp analogs reveal that only Trp and its synthetic anlog α-methyl Trp, inhibit degron accessibility by structuring a C-terminal region.
This links ligand chemistry to decision-making by the UPS.
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Many thanks to Brenda, Basti, all co-authors @mpibiochem.bsky.social and collaborators Simon and Benoît @ludwigcancer.bsky.social!
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When Trp is limiting, TDO2 is subject to proteasomal degradation to avert tryptophanemia.
By combining CRISPRi screening, biochemistry and cryo-EM, we discovered how Trp is perceived by binding to an exosite on TDO2 to control its phosphorylation-dependent ubiquitylation.
3/6
Formation & function of #MembranelessOrganelles! #CryoET structures of #proteasome storage granules inside cells!
Read our paper @cp-cell.bsky.social!
❕Publication: doi.org/10.1016/j.ce...
❕Press Release: www.biochem.mpg.de/en/pressroom
@uoftmedicine.bsky.social
@erc.europa.eu #UPSmeetMet
