Ubiquitin Signalling
Group Leader:
Prof Danny Huang
Post-translational modification with ubiquitin (Ub) initiated by sequential actions of Ub-activating enzyme (E1), Ub-conjugating enzyme (E2) and Ub ligase (E3) regulates diverse cellular processes, including signal transduction, cell cycle progression, apoptosis and gene transcription. Deregulation in the Ub pathway is often associated with human pathogenesis, including cancer. Our group uses structural biology and biochemical approaches to study the enzymes in the Ub pathway to understand their regulation, mechanistic function and mutation-induced deregulation. We anticipate that the knowledge gained from our structural studies will assist in the development of selective therapeutic targets within the Ub pathway.
Lab Reports
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Recent Publications
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Lab Members
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Recent Publications
2026
Spain F, Gimenez D, Acevedo-Jake AM, Mylemans B, Brooks NJ, Korona B, Huang DT, Edwards TA, Leney AC, Itzhaki L, Woolfson DN, Wilson AJ. De novo grafted coiled-coil peptides as p53/hDM2 inhibitors. RSC Chem Biol. 2026.
2025
Ahmed SF, Anand J, Zhang W, Buetow L, Rishi L, Mitchell L, Bohlen J, Lilla S, Sibbet GJ, Nixon C, Patel A, Majorek KA, Zanivan S, Bustamante JC, Sidhu SS, Blyth K, Huang DT. Locking CBL TKBD in its native conformation presents a novel therapeutic opportunity in mutant CBL-dependent leukemia. Molecular Therapy.
Acevedo-Jake AM, Mylemans B, Kay DF, Zhang P, Korona B, Rhys GG, Leney AC, Huang DT, Edwards TA, Itzhaki L, Woolfson DN, Wilson AJ. Grafted Coiled-Coil Peptides as Multivalent Scaffolds for Protein Recognition. ACS Chem Biol. 2025.
Cooke SF, Wright TA, Lappin G, Kyurkchieva E, Sin YY, Ling J, Zorn A, O’Gorman B, Banyard W, Chang CJ, Wheadon H, Huang DT, Baillie GS, Blair CM. Targeting MDM2 homodimer and heterodimer disruption with DRx-098D in TP53 wild-type and mutant cancer cells. Mol Ther Oncol. 2025;33(3):201029.
Morgan DC, McDougall L, Knuhtsen A, Buetow L, Steven CF, Shepperson OA, Huang DT, Hulme AN, Jamieson AG. Raman active diyne-girder conformationally constrained p53 stapled peptides bind to MDM2 for visualisation without fluorophores. RSC Chem Biol. 2025.
Nakasone MA, Buetow L, Gabrielsen M, Ahmed SF, Majorek KA, Sibbet GJ, Smith BO, Huang DT. Tuning ubiquitin transfer by RING E3 ubiquitin ligases through the linchpin residue. Life Sci Alliance. 2025;8(10).
Wicks AT, Buetow L, Suzuki T, Schmidt T, Lilla S, Macmillan-Jones A, Turney J, Gohlke A, Bushell M, Hock AK, Huang DT. CBL ubiquitin ligase targets translation as a degrader E3. Chem Sci. 2025.
2024
Bohlen J, Bagarić I, Vatovec T, Ogishi M, Ahmed SF, Cederholm A, Buetow L, Sobrino S, Le Floc’h C, Arango-Franco CA, Seabra L, Michelet M, Barzaghi F, Leardini D, Saettini F, Vendemini F, Baccelli F, Catala A, Gambineri E, Veltroni M, Aguilar de la Red Y, Rice GI, Consonni F, Berteloot L, Largeaud L, Conti F, Roullion C, Masson C, Bessot B, Seeleuthner Y, Le Voyer T, Rinchai D, Rosain J, Neehus AL, Erazo-Borrás L, Li H, Janda Z, Cho EJ, Muratore E, Soudée C, Lainé C, Delabesse E, Goulvestre C, Ma CS, Puel A, Tangye SG, André I, Bole-Feysot C, Abel L, Erlacher M, Zhang SY, Béziat V, Lagresle-Peyrou C, Six E, Pasquet M, Alsina L, Aiuti A, Zhang P, Crow YJ, Landegren N, Masetti R, Huang DT, Casanova JL, Bustamante J. Autoinflammation in patients with leukocytic CBL loss of heterozygosity is caused by constitutive ERK-mediated monocyte activation. J Clin Invest. 2024;134(20).
Dearlove EL, Chatrin C, Buetow L, Ahmed SF, Schmidt T, Bushell M, Smith BO, Huang DT. DTX3L ubiquitin ligase ubiquitinates single-stranded nucleic acids. Elife. 2024;13.
Vosbein P, Paredes Vergara P, Huang DT, Thomson AR. AlphaFold Ensemble Competition Screens Enable Peptide Binder Design with Single-Residue Sensitivity. ACS Chem Biol. 2024;19(10):2198-2205.
Vosbein P, Vergara PP, Huang DT, Thomson AR. An engineered ubiquitin binding coiled coil peptide. Chem Sci. 2024.
Vringer E, Heilig R, Riley JS, Black A, Cloix C, Skalka G, Montes-Gómez AE, Aguado A, Lilla S, Walczak H, Gyrd-Hansen M, Murphy DJ, Huang DT, Zanivan S, Tait SW. Mitochondrial outer membrane integrity regulates a ubiquitin-dependent and NF-κB-mediated inflammatory response. EMBO J. 2024.
2023
Chen H, Bai Y, Kobayashi M, Xiao S, Cai W, Barajas S, Chen S, Miao J, Meke FN, Vemula S, Ropa JP, Croop JM, Boswell HS, Wan J, Jia Y, Liu H, Li LS, Altman JK, Eklund EA, Ji P, Tong W, Band H, Huang DT, Platanias LC, Zhang ZY, Liu Y. PRL2 phosphatase enhances oncogenic FLT3 signaling via dephosphorylation of the E3 ubiquitin ligase CBL at tyrosine 371. Blood. 2023;141:244-259.
Chen H, Bai Y, Kobayashi M, Xiao S, Barajas S, Cai W, Chen S, Miao J, Nguele Meke F, Yao C, Yang Y, Strube K, Satchivi O, Sun J, Ronnstrand L, Croop JM, Boswell HS, Jia Y, Liu H, Li LS, Altman JK, Eklund EA, Sukhanova M, Ji P, Tong W, Band H, Huang DT, Platanias LC, Zhang ZY, Liu Y. PRL2 phosphatase promotes oncogenic KIT signaling in leukemia cells through modulating CBL phosphorylation. Mol Cancer Res. 2023.
Nikolatou K, Sandilands E, Román-Fernández A, Cumming EM, Freckmann E, Lilla S, Buetow L, McGarry L, Neilson M, Shaw R, Strachan D, Miller C, Huang DT, McNeish IA, Norman JC, Zanivan S, Bryant DM. PTEN deficiency exposes a requirement for an ARF GTPase module for integrin-dependent invasion in ovarian cancer. The EMBO Journal. 2023;n/a:e113987.
Schmidt T, Dabrowska A, Waldron JA, Hodge K, Koulouras G, Gabrielsen M, Munro J, Tack DC, Harris G, McGhee E, Scott D, Carlin Leo M, Huang D, Le Quesne J, Zanivan S, Wilczynska A, Bushell M. eIF4A1-dependent mRNAs employ purine-rich 5’UTR sequences to activate localised eIF4A1-unwinding through eIF4A1-multimerisation to facilitate translation. Nucleic Acids Research. 2023; 51: 1859–1879
Villar VH, Allega MF, Deshmukh R, Ackermann T, Nakasone MA, Vande Voorde J, Drake TM, Oetjen J, Bloom A, Nixon C, Müller M, May S, Tan EH, Vereecke L, Jans M, Blancke G, Murphy DJ, Huang DT, Lewis DY, Bird TG, Sansom OJ, Blyth K, Sumpton D, Tardito S. Hepatic glutamine synthetase controls N5-methylglutamine in homeostasis and cancer. Nature Chemical Biology. 2023;19:292-300.
2022
Kowalczyk D, Nakasone MA, Smith BO, Huang DT. Bivalent binding of p14ARF to MDM2 RING and acidic domains inhibits E3 ligase function. Life Sci Alliance. 2022;5(12).
Nakasone MA, Majorek KA, Gabrielsen M, Sibbet GJ, Smith BO, Huang DT. Structure of UBE2K–Ub/E3/polyUb reveals mechanisms of K48-linked Ub chain extension. Nature Chemical Biology. 2022; 18:422–431
Nikolatou K, Sandilands E, Roman-Fernandez A, Cumming EM, Freckmann EC, Lilla S, Buetow L, McGarry L, Neilson M, Shaw R, Strachan D, Miller C, Huang DT, McNeish IA, Norman JC, Zanivan S, Bryant D. PTEN deficiency exposes a requirement for an ARF GTPase module in integrin-dependent invasion in ovarian cancer. bioRxiv. 2022;Volume:2022.2011.2029.518198.
2021
Ahmed SF, Buetow L, Gabrielsen M, Lilla S, Sibbet GJ, Sumpton D, Zanivan S, Hedley A, Clark W, Huang DT. E3 ligase-inactivation rewires CBL interactome to elicit oncogenesis by hijacking RTK-CBL-CIN85 axis. Oncogene. 2021;40:2149-2164.
Humpton TJ, Nomura K, Weber J, Magnussen HM, Hock AK, Nixon C, Dhayade S, Stevenson D, Huang DT, Strathdee D, Blyth K, Vousden KH. Differential requirements for MDM2 E3 activity during embryogenesis and in adult mice. Genes & development. 2021;35:117-132.
Magnussen HM, Huang DT. Identification of a catalytic active but non-aggregating MDM2 RING domain variant. J Mol Biol. 2021; 433:166807.
2020
Ahmed SF, Buetow L, Gabrielsen M, Lilla S, Chatrin C, Sibbet GJ, Zanivan S, Huang DT. DELTEX2 C-terminal domain recognizes and recruits ADP-ribosylated proteins for ubiquitination. Sci Adv. 2020;6(34):eabc0629.
Chatrin C, Gabrielsen M, Buetow L, Nakasone MA, Ahmed SF, Sumpton D, Sibbet GJ, Smith BO, Huang DT. Structural insights into ADP-ribosylation of ubiquitin by Deltex family E3 ubiquitin ligases. Sci Adv. 2020;6(38): eabc0418
Magnussen HM, Ahmed SF, Sibbet GJ, Hristova VA, Nomura K, Hock AK, Archibald LJ, Jamieson AG, Fushman D, Vousden KH, Weissman AM, Huang DT. Structural basis for DNA damage-induced phosphoregulation of MDM2 RING domain. Nat Commun. 2020; 11: 2094
2019
Gabrielsen M, Buetow L, Kowalczyk D, Zhang W, Sidhu SS, Huang DT. Identification and Characterization of Mutations in Ubiquitin Required for Non-covalent Dimer Formation. Structure. 2019; 27: 1452-9
Patel A, Sibbet GJ, Huang DT. Structural insights into non-covalent ubiquitin activation of the cIAP1-UbcH5B∼ubiquitin complex. Journal of Biological Chemistry 2019; 294: 1240-1249.
2018
Buetow L, Gabrielsen M, Huang DT. Single-Turnover RING/U-Box E3-Mediated Lysine Discharge Assays. Methods Mol Biol 2018; 1844: 19-31
Marcianò G, Da Vela S, Tria G, Svergun DI, Byron O, Huang DT. Structure specific recognition protein-1 (SSRP1) is an elongated homodimer that binds histones. J Biol Chem. 2018; 293, 10071-10083.
2017
Gabrielsen M, Buetow L, Nakasone MA, Ahmed SF, Sibbet GJ, Smith BO, Zhang W, Sidhu SS, Huang DT. A General Strategy for Discovery of Inhibitors and Activators of RING and U-box E3 Ligases with Ubiquitin Variants. Mol Cell 2017; 68: 456-70 e10
Nomura K, Klejnot M, Kowalczyk D, Hock AK, Sibbet GJ, Vousden KH, Huang DT. Structural analysis of MDM2 RING separates degradation from regulation of p53 transcription activity. Nat Struct Mol Biol 2017; 24: 578-87
2016
Buetow L, Tria G, Ahmed SF, Hock A, Dou H, Sibbet GJ, Svergun DI, Huang DT. Casitas B-lineage lymphoma linker helix mutations found in myeloproliferative neoplasms affect conformation. BMC Biol 14: 76, 2016
Marciano G, Huang DT. Structure of the human histone chaperone FACT Spt16 N-terminal domain. Acta Crystallogr F 72: 121-8, 2016
Buetow L, Huang DT. Structural insights into the catalysis and regulation of E3 ubiquitin ligases. Nat Rev Mol Cell Bio 17: 626-42, 2016
Nakasone MA, Huang DT. Ubiquitination accomplished: E1 and E2 enzymes were not necessary. Mol Cell 62: 807-9, 2016
Associate Scientist
Lori Buetow*
Information about this team member’s research interests, experience, and background will be added soon. Please check back for updates.
Research Scientist
Lorraine Glennie
Over the course of my Bachelor’s degree at the University of Edinburgh (2014-2018) and my Masters degree at the University of Glasgow (2018-2019), I developed an interest in protein signalling and post-translational protein modification. I carried out my PhD with Prof. Gopal Sapkota at the MRC Protein Phosphorylation and Ubiquitylation Unit in Dundee (2020-2024) where I characterised casein kinase 1α (CK1α) function in cells and explored different methods of targeted protein degradation (TPD) using proteolysis-targeting chimeras (PROTACs) and molecular glues. I started my postdoc with Prof. Danny Huang in October 2025 with a primary focus of targeting p53 mutants in cancer cells using TPD modalities. I am originally from Glasgow and enjoy attending music concerts and festivals throughout Scotland, reading fiction novels and spending time with my family.
Scientific Officer
Michael Mcilwraith
I completed my B.Sc. degree in Molecular Biology and Ph.D. in biochemistry at the University of Glasgow and then did a post-doc at the University of Michigan, USA. I joined Cancer Research UK and did a post-doc, became a Senior Scientific Officer and then a Principal Scientific Officer in the lab of Steve West working on DNA repair and cancer. I joined the Beatson Institute in 2014 working for Shehab Ismail and then joined Danny Huang’s lab in 2021 working on protein ubiquitination and cancer. Outside the lab I enjoy walking, reading, and watching movies.
Scientific Officer
Feroj Syed*
Information about this team member’s research interests, experience, and background will be added soon. Please check back for updates.
Graduate Student
Emily Dearlove
I completed my Bachelor’s in Biochemistry at the University of York, including spending a year long placement in industry at Sosei Heptares in Cambridge where I investigated GPCRs using site directed mutagenesis to gain further insight into their ligand binding modes. I joined Danny’s lab as a PhD student in 2022 where I am investigating the ubiquitination activity of RING E3 ligases, particularly focusing on non-proteinaceous substrates of ubiquitination. Outside of the lab, I enjoy exploring the countryside, knitting and watching Formula 1.
Graduate Student
Shijie Wang*
Information about this team member’s research interests, experience, and background will be added soon. Please check back for updates.