5LP8

Crystal structure of an asymmetric dimer of the ubiquitin ligase HUWE1

Summary for 5LP8

• Entry DOI: 10.2210/pdb5lp8/pdb
• Descriptor: E3 ubiquitin-protein ligase HUWE1 (2 entities in total)
• Functional Keywords: ubiquitin ligase, e3 enzyme, hect, ligase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : Q7Z6Z7
• Total number of polymer chains: 2
• Total formula weight: 105903.89

Authors

Sander, B.,Lorenz, S.G. (deposition date: 2016-08-12, release date: 2017-02-22, Last modification date: 2024-01-10)

Primary citation

Sander, B.,Xu, W.,Eilers, M.,Popov, N.,Lorenz, S.
A conformational switch regulates the ubiquitin ligase HUWE1.
Elife, 6:-, 2017

PubMed Abstract: 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 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.

PubMed: 28193319
DOI: 10.7554/eLife.21036

Experimental method

X-RAY DIFFRACTION (2.7 Å)