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  GID E3 ligase supramolecular chelate assembly configures multipronged ubiquitin targeting of an oligomeric metabolic enzyme

Sherpa, D., Chrustowicz, J., Qiao, S., Langlois, C. R., Hehl, L. A., Gottemukkala, K. V., et al. (2021). GID E3 ligase supramolecular chelate assembly configures multipronged ubiquitin targeting of an oligomeric metabolic enzyme. Molecular Cell, 81(11), 2445-2459.e13. doi:10.1016/j.molcel.2021.03.025.

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 Creators:
Sherpa, Dawafuti1, Author           
Chrustowicz, Jakub1, Author           
Qiao, Shuai1, Author           
Langlois, Christine R.1, Author           
Hehl, Laura A.1, Author           
Gottemukkala, Karthik Varma1, Author           
Hansen, Fynn M.2, Author           
Karayel, Ozge2, Author           
von Gronau, Susanne1, Author           
Prabu, J. Rajan1, Author           
Mann, Matthias2, Author           
Alpi, Arno F.1, Author           
Schulman, Brenda A.1, Author           
Affiliations:
1Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society, ou_2466699              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              

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Free keywords: CATABOLITE DEGRADATION; SACCHAROMYCES-CEREVISIAE; COMPLEX; PROTEIN; FRUCTOSE-1,6-BISPHOSPHATASE; PROTEASOME; MUSKELIN; YEAST; INACTIVATION; MECHANISMBiochemistry & Molecular Biology; Cell Biology;
 Abstract: How are E3 ubiquitin ligases configured to match substrate quaternary structures? Here, by studying the yeast GID complex (mutation of which causes deficiency in glucose-induced degradation of gluconeogenic enzymes), we discover supramolecular chelate assembly as an E3 ligase strategy for targeting an oligomeric substrate. Cryoelectron microscopy (cryo-EM) structures show that, to bind the tetrameric substrate fructose-1,6-bisphosphatase (Fbp1), two minimally functional GID E3s assemble into the 20-protein Chelator-GID(SR4), which resembles an organometallic supramolecular chelate. The Chelator-GID(SR4) assembly avidly binds multiple Fbp1 degrons so that multiple Fbp1 protomers are simultaneously ubiquitylated at lysines near the allosteric and substrate binding sites. Importantly, key structural and biochemical features, including capacity for supramolecular assembly, are preserved in the human ortholog, the CTLH E3. Based on our integrative structural, biochemical, and cell biological data, we propose that higher-order E3 ligase assembly generally enables multipronged targeting, capable of simultaneously incapacitating multiple protomers and functionalities of oligomeric substrates.

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Language(s): eng - English
 Dates: 2021
 Publication Status: Published in print
 Pages: 28
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Degree: -

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Title: Molecular Cell
Source Genre: Journal
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Publ. Info: Cambridge, Mass. : Cell Press
Pages: - Volume / Issue: 81 (11) Sequence Number: - Start / End Page: 2445 - 2459.e13 Identifier: ISSN: 1097-2765
CoNE: https://pure.mpg.de/cone/journals/resource/954925610929