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Structural dynamics of E6AP E3 ligase HECT domain and involvement of flexible hinge loop in ubiquitin chain synthesis mechanism

Kazusa Takeda, Ikumi Muro, Fuminori Kobayashi, Holger Flechsig, Noriyuki Kodera, Toshio Ando, Hiroki Konno
doi: https://doi.org/10.1101/2022.11.18.516873
Kazusa Takeda
1Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa 920-1192, Japan
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Ikumi Muro
1Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa 920-1192, Japan
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Fuminori Kobayashi
1Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa 920-1192, Japan
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Holger Flechsig
2WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
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Noriyuki Kodera
2WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
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Toshio Ando
2WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
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Hiroki Konno
2WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
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  • For correspondence: hkonno@se.kanazawa-u.ac.jp
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Abstract

Ubiquitin (Ub) ligases E3 are an important factor in selecting target proteins for ubiquitination and determining the type of polyubiquitin chains on the target proteins. In the HECT (homologous to E6AP C-terminus)-type E3 ligases, the HECT domain is composed of an N-lobe containing the E2-binding site and a C-lobe containing the catalytic Cys residue that forms a thioester bond with Ub. These two lobes are connected by a flexible hinge loop. The large conformational rearrangement of the HECT domain via the flexible hinge loop is essential for HECT-type E3-mediated Ub transfer from E2 to a target protein. However, detailed insights into the structural dynamics of this type of E3 ligases remain unclear. Here, we provide the first direct demonstration of structural dynamics of the E6AP HECT domain using high-speed atomic force microscopy. We also investigated structural dynamics of hinge loop flexibility restricted HECT domain, and we found that flexibility of the E6AP hinge loop has a great impact not only on its structural dynamics but also on the formation of free Ub chains mediated by E3-E3 interactions.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted November 18, 2022.
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Structural dynamics of E6AP E3 ligase HECT domain and involvement of flexible hinge loop in ubiquitin chain synthesis mechanism
Kazusa Takeda, Ikumi Muro, Fuminori Kobayashi, Holger Flechsig, Noriyuki Kodera, Toshio Ando, Hiroki Konno
bioRxiv 2022.11.18.516873; doi: https://doi.org/10.1101/2022.11.18.516873
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Structural dynamics of E6AP E3 ligase HECT domain and involvement of flexible hinge loop in ubiquitin chain synthesis mechanism
Kazusa Takeda, Ikumi Muro, Fuminori Kobayashi, Holger Flechsig, Noriyuki Kodera, Toshio Ando, Hiroki Konno
bioRxiv 2022.11.18.516873; doi: https://doi.org/10.1101/2022.11.18.516873

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