Alina Thielen alinathielen - Bluesky Statics

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

28.01.2026 16:39 — 👍 68 🔁 26 💬 0 📌 2

Many thanks to Brenda, Basti, all co-authors @mpibiochem.bsky.social and collaborators Simon and Benoît @ludwigcancer.bsky.social!

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13.01.2026 13:49 — 👍 0 🔁 0 💬 0 📌 0

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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13.01.2026 13:49 — 👍 1 🔁 0 💬 1 📌 0

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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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.

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13.01.2026 13:49 — 👍 1 🔁 0 💬 1 📌 0

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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A CK2-FBXW11 kinase-E3 ubiquitin ligase cascade is a metabolic sensor regulating Tryptophan 2,3-dioxygenase stability Small molecules toggling the ubiquitin-proteasome system (UPS) are powerful regulators of protein degradation. Yet, mechanistic knowledge of how endogenous ligands gate UPS decisions remains rudimentary. Here, we define control of UPS access to Tryptophan-2,3-dioxygenase (TDO2), which converts the essential amino acid tryptophan (Trp) to N-formylkynurenine. When Trp concentrations are limiting, TDO2 is degraded to avert tryptophanemia. Using CRISPRi screening and biochemistry, we identify a CK2-FBXW11 kinase-E3 ligase cascade that generates and recognizes tandem TDO2 phosphodegrons when not protected by Trp. Trp binding to an exosite safeguards TDO2 from phosphorylation-dependent ubiquitylation. Effects of Trp analogs on CK2-FBXW11-dependent ubiquitylation indicated that the indole, amino, and carboxylate groups are necessary for substrate shielding. Cryo-EM reveals how these moieties order a region proximal to the phosphodegrons; without Trp, this segment is flexible, enabling phosphorylation-coupled ubiquitylation. Overall, our data uncovered an endogenous small molecule allosterically stabilizing its own metabolizing enzyme through protection from a phosphorylation-ubiquitylation cascade. ### Competing Interest Statement B.A.S. is a member of the scientific advisory boards of Proxygen and Lyterian. The other authors declare no competing interests. Max Planck Society, https://ror.org/01hhn8329 European Union, ERC AdvG, UPSmeetMet, 101098161 to BAS Boehringer Ingelheim Fonds, https://ror.org/00dkye506

New year, new preprint! 🎊

We are excited to share our recent work on #E3 ligase regulation in #metabolism!

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

#ubiquitin #targetedproteindegradation #chemicalbiology

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13.01.2026 13:49 — 👍 43 🔁 17 💬 1 📌 5

When RNA Degradation 🤝 meets 🤝 Protein Degradation! tinyurl.com/E3TDMD In a collaboration of @bartellab.bsky.social and Schulman lab, we show that, in target-directed microRNA degradation (TDMD), 2-RNA-factors recruit an E3 ligase and induce the degradation of not only a protein but also RNA (1/5).

06.01.2026 08:04 — 👍 117 🔁 50 💬 1 📌 4

TRIP12 structures reveal HECT E3 formation of K29 linkages and branched ubiquitin chains - Nature Structural & Molecular Biology 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...

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...

26.05.2025 09:36 — 👍 44 🔁 17 💬 4 📌 3

UbiREAD deciphers proteasomal degradation code of homotypic and branched K48 and K63 ubiquitin chains Ubiquitin chains determine the fates of their modified proteins, including proteasomal degradation. Kiss et al. present UbiREAD, a technology to monitor cellular degradation and deubiquitination at hi...

Super excited to share our latest work on deciphering the #Ubiquitin Code

“𝗨𝗯𝗶𝗥𝗘𝗔𝗗 𝗱𝗲𝗰𝗶𝗽𝗵𝗲𝗿𝘀 𝗽𝗿𝗼𝘁𝗲𝗮𝘀𝗼𝗺𝗮𝗹 𝗱𝗲𝗴𝗿𝗮𝗱𝗮𝘁𝗶𝗼𝗻 𝗰𝗼𝗱𝗲 𝗼𝗳 𝗵𝗼𝗺𝗼𝘁𝘆𝗽𝗶𝗰 𝗮𝗻𝗱 𝗯𝗿𝗮𝗻𝗰𝗵𝗲𝗱 𝗞48 𝗮𝗻𝗱 𝗞63 𝘂𝗯𝗶𝗾𝘂𝗶𝘁𝗶𝗻 𝗰𝗵𝗮𝗶𝗻𝘀”

@cp-molcell.bsky.social

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www.cell.com/molecular-ce...

24.03.2025 14:54 — 👍 131 🔁 44 💬 16 📌 4

Posts by Alina Thielen (@alinathielen.bsky.social)