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  Beta-sheet augmentation is a conserved mechanism of priming HECT E3 ligases for ubiquitin ligation.

Jäckl, M., Stollmaier, C., Strohäker, T., Hyz, K., Maspero, E., Polo, S., et al. (2018). Beta-sheet augmentation is a conserved mechanism of priming HECT E3 ligases for ubiquitin ligation. Journal of Molecular Biology, 430(18), 3218-3233. doi:10.1016/j.jmb.2018.06.044.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0002-471A-2 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-69F8-0
Genre: Journal Article

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Jäckl, M., Author
Stollmaier, C., Author
Strohäker, T.1, Author              
Hyz, K., Author
Maspero, E., Author
Polo, S., Author
Wiesner, S., Author
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1Research Group of Protein Structure Determination using NMR, MPI for Biophysical Chemistry, Max Planck Society, ou_578571              

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Free keywords: Huwe1; Smurf2; HECT domain; thioester intermediate; NMR spectroscopy
 Abstract: Ubiquitin (Ub) ligases (E3s) catalyze the attachment of Ub chains to target proteins and thereby regulate a wide array of signal transduction pathways in eukaryotes. In HECT-type E3s, Ub first forms a thioester intermediate with a strictly conserved Cys in the C-lobe of the HECT domain and is then ligated via an isopeptide bond to a Lys residue in the substrate or a preceding Ub in a poly-Ub chain. To date, many key aspects of HECT-mediated Ub transfer have remained elusive. Here, we provide structural and functional insights into the catalytic mechanism of the HECT-type ligase Huwe1 and compare it to the unrelated, K63-specific Smurf2 E3, a member of the Nedd4 family. We found that the Huwe1 HECT domain, in contrast to Nedd4-family E3s, prioritizes K6- and K48-poly-Ub chains and does not interact with Ub in a non-covalent manner. Despite these mechanistic differences, we demonstrate that the architecture of the C-lobe Ub intermediate is conserved between Huwe1 and Smurf2 and involves a reorientation of the very C-terminal residues. Moreover, in Nedd4 E3s and Huwe1, the individual sequence composition of the Huwe1 C-terminal tail modulates ubiquitination activity, without affecting thioester formation. In sum, our data suggest that catalysis of HECT ligases hold common features, such as the 13-sheet augmentation that primes the enzymes for ligation, and variable elements, such as the sequence of the HECT C-terminal tail, that fine-tune ubiquitination activity and may aid in determining Ub chain specificity by positioning the substrate or acceptor Ub.

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Language(s): eng - English
 Dates: 2018-06-282018-09-14
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1016/j.jmb.2018.06.044
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Title: Journal of Molecular Biology
Source Genre: Journal
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Pages: - Volume / Issue: 430 (18) Sequence Number: - Start / End Page: 3218 - 3233 Identifier: -