A conformational switch regulates the ubiquitin ligase HUWE1
Please always quote using this URN: urn:nbn:de:bvb:20-opus-171862
- The human ubiquitin ligase HUWE1 has key roles in tumorigenesis, yet it is unkown how its activity is regulated. We present the crystal structure of a C-terminal part of HUWE1, including the catalytic domain, and reveal an asymmetric auto-inhibited dimer. We show that HUWE1 dimerizes in solution and self-associates in cells, and that both occurs through the crystallographic dimer interface. We demonstrate that HUWE1 is inhibited in cells and that it can be activated by disruption of the dimer interface. We identify a conserved segment in HUWE1The human ubiquitin ligase HUWE1 has key roles in tumorigenesis, yet it is unkown how its activity is regulated. We present the crystal structure of a C-terminal part of HUWE1, including the catalytic domain, and reveal an asymmetric auto-inhibited dimer. We show that HUWE1 dimerizes in solution and self-associates in cells, and that both occurs through the crystallographic dimer interface. We demonstrate that HUWE1 is inhibited in cells and that it can be activated by disruption of the dimer interface. We identify a conserved segment in HUWE1 that counteracts dimer formation by associating with the dimerization region intramolecularly. Our studies reveal, intriguingly, that the tumor suppressor p14ARF binds to this segment and may thus shift the conformational equilibrium of HUWE1 toward the inactive state. We propose a model, in which the activity of HUWE1 underlies conformational control in response to physiological cues—a mechanism that may be exploited for cancer therapy.…
Author: | Bodo Sander, Wenshan Xu, Martin Eilers, Nikita Popov, Sonja Lorenz |
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URN: | urn:nbn:de:bvb:20-opus-171862 |
Document Type: | Journal article |
Faculties: | Medizinische Fakultät / Klinik und Poliklinik für Strahlentherapie |
Medizinische Fakultät / Theodor-Boveri-Institut für Biowissenschaften | |
Medizinische Fakultät / Medizinische Klinik und Poliklinik II | |
Fakultät für Biologie / Rudolf-Virchow-Zentrum | |
Language: | English |
Parent Title (English): | eLife |
Year of Completion: | 2017 |
Volume: | 6 |
Article Number: | e21036 |
Source: | eLife (2017) 6:e21036 DOI: 10.7554/eLife.21036 |
DOI: | https://doi.org/10.7554/eLife.21036 |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Tag: | Enzyme Regulation; HECT Ligase; HUWE1; Medicine; Molecular Biophysics; P14ARF; Structural Biology; Ubiquitin; X-Ray Chrystallography |
Release Date: | 2021/02/03 |
Licence (German): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |