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RINGE3 SIGNED

Structural and mechanistic insights into RING E3-mediated ubiquitination

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EC-Contrib. €

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Project "RINGE3" data sheet

The following table provides information about the project.

Coordinator
BEATSON INSTITUTE FOR CANCER RESEARCH LBG 

Organization address
address: SWITCHBACK ROAD GARSCUBE ESTATE
city: BEARSDEN
postcode: G61 1BD
website: http://www.beatson.gla.ac.uk/

contact info
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name: n.a.
surname: n.a.
function: n.a.
email: n.a.
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 Coordinator Country United Kingdom [UK]
 Project website http://www.beatson.gla.ac.uk/Cancer-Metabolism-Growth-and-Survival/danny-huang-ubiquitin-signalling.html
 Total cost 2˙000˙000 €
 EC max contribution 2˙000˙000 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2014-CoG
 Funding Scheme ERC-COG
 Starting year 2015
 Duration (year-month-day) from 2015-05-01   to  2020-04-30

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    BEATSON INSTITUTE FOR CANCER RESEARCH LBG UK (BEARSDEN) coordinator 2˙000˙000.00

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 Project objective

Ubiquitin (Ub) conjugation regulates a myriad of cellular processes in the eukaryotic cell. Ub-ligases (E3) play a pivotal role in deciding the substrate’s fate and function by catalyzing the transfer of Ub from Ub-conjugating enzyme (E2) to a substrate protein lysine sidechain. Successive rounds of E3-catalyzed substrate ubiquitination lead to the formation of poly-Ub chains or multi-monoubiquitination, which direct the substrate to different biological fates such as degradation by the 26S proteasome. RING E3s comprise the largest family of E3s with approximately 600 members in humans. Over the last fifteen years, structural biology and biochemical studies have paved the way for understanding how RING E3s interact with E2s and substrates, and how they are regulated. Recently my group has trapped the crystal structure of a RING E3 bound to an E2 covalently-linked to Ub (E2~Ub), thus providing a molecular snapshot of how RING E3 optimizes E2~Ub for catalysis. Despite these advances, the mechanisms of RING E3-catalyzed ubiquitination are not completely understood. Here, we propose to investigate three key aspects of RING E3 functions. First, we will determine structures of several RING E3s bound to E2~Ub to dissect the molecular basis for RING E3-E2~Ub selectivity. Second, our recent structure of a RING E3, Cbl-b, bound to E2~Ub and a substrate peptide provides a starting point for structural determination of a more challenging RING E3-E2~Ub-intact substrate complex to elucidate the mechanisms of substrate ubiquitination. Third, we have developed an ubiquitinated Cbl-substrate mimetic to study the mechanisms of RING E3-catalyzed poly-ubiquitination using structural and biochemical approaches. Expected results will greatly expand our knowledge of RING E3-mediated ubiquitination and will foster strategies in exploiting E3s for therapeutic development, since deregulation of E3s underlies many diseases including cancers.

 Publications

year authors and title journal last update
List of publications.
2019 Amrita Patel, Gary J. Sibbet, Danny T. Huang
Structural insights into non-covalent ubiquitin activation of the cIAP1-UbcH5B∼ubiquitin complex
published pages: 1240-1249, ISSN: 0021-9258, DOI: 10.1074/jbc.ra118.006045
Journal of Biological Chemistry 294/4 2020-04-14
2019 Mads Gabrielsen, Lori Buetow, Dominika Kowalczyk, Wei Zhang, Sachdev S.Sidhu and Danny T.Huang
Identification and characterization of mutations in ubiquitin required for non-covalent dimer formation
published pages: 1452-1459.e4, ISSN: 0969-2126, DOI: 10.1016/j.str.2019.06.008
Structure 27/9 2020-04-14
2018 Gabriele Marcianò, Stefano Da Vela, Giancarlo Tria, Dmitri I. Svergun, Olwyn Byron, Danny T. Huang
Structure specific recognition protein-1 (SSRP1) is an elongated homodimer that binds histones
published pages: jbc.RA117.000994, ISSN: 0021-9258, DOI: 10.1074/jbc.RA117.000994
Journal of Biological Chemistry 2020-04-14
2016 Mark A. Nakasone, Danny T. Huang
Ubiquitination Accomplished: E1 and E2 Enzymes Were Not Necessary
published pages: 807-809, ISSN: 1097-2765, DOI: 10.1016/j.molcel.2016.06.001
Molecular Cell 62/6 2020-04-14
2017 Koji Nomura, Marta Klejnot, Dominika Kowalczyk, Andreas K Hock, Gary J Sibbet, Karen H Vousden, Danny T Huang
Structural analysis of MDM2 RING separates degradation from regulation of p53 transcription activity
published pages: 578-587, ISSN: 1545-9993, DOI: 10.1038/nsmb.3414
Nature Structural & Molecular Biology 24/7 2020-04-14
2016 Lori Buetow, Giancarlo Tria, Syed Feroj Ahmed, Andreas Hock, Hao Dou, Gary J. Sibbet, Dmitri I. Svergun, Danny T. Huang
Casitas B-lineage lymphoma linker helix mutations found in myeloproliferative neoplasms affect conformation
published pages: , ISSN: 1741-7007, DOI: 10.1186/s12915-016-0298-6
BMC Biology 14/1 2020-04-14
2016 G. Marcianò, D. T. Huang
Structure of the human histone chaperone FACT Spt16 N-terminal domain
published pages: 121-128, ISSN: 2053-230X, DOI: 10.1107/S2053230X15024565
Acta Crystallographica Section F Structural Biology Communications 72/2 2020-04-14
2017 Mads Gabrielsen, Lori Buetow, Mark A. Nakasone, Syed Feroj Ahmed, Gary J. Sibbet, Brian O. Smith, Wei Zhang, Sachdev S. Sidhu, Danny T. Huang
A General Strategy for Discovery of Inhibitors and Activators of RING and U-box E3 Ligases with Ubiquitin Variants
published pages: 456-470.e10, ISSN: 1097-2765, DOI: 10.1016/j.molcel.2017.09.027
Molecular Cell 68/2 2020-04-14
2016 Lori Buetow, Danny T. Huang
Structural insights into the catalysis and regulation of E3 ubiquitin ligases
published pages: 626-642, ISSN: 1471-0072, DOI: 10.1038/nrm.2016.91
Nature Reviews Molecular Cell Biology 17/10 2020-04-14

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