5TJ8

Structure of WWP2 WW2-2,3-linker-HECT (no WW2 observed)

Summary for 5TJ8

• Entry DOI: 10.2210/pdb5tj8/pdb
• Related: 5TJ7 5TJQ
• Descriptor: NEDD4-like E3 ubiquitin-protein ligase WWP2,NEDD4-like E3 ubiquitin-protein ligase WWP2, SODIUM ION (3 entities in total)
• Functional Keywords: wwp2, hect domain, ww2, wwp1, itch, autoinhibition, transferase
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus : O00308
• Total number of polymer chains: 1
• Total formula weight: 53464.53

Authors

Chen, Z.,Gabelli, S.B. (deposition date: 2016-10-03, release date: 2017-06-07, Last modification date: 2023-10-04)

Primary citation

Chen, Z.,Jiang, H.,Xu, W.,Li, X.,Dempsey, D.R.,Zhang, X.,Devreotes, P.,Wolberger, C.,Amzel, L.M.,Gabelli, S.B.,Cole, P.A.
A Tunable Brake for HECT Ubiquitin Ligases.
Mol. Cell, 66:345-357.e6, 2017

PubMed Abstract: The HECT E3 ligases ubiquitinate numerous transcription factors and signaling molecules, and their activity must be tightly controlled to prevent cancer, immune disorders, and other diseases. In this study, we have found unexpectedly that peptide linkers tethering WW domains in several HECT family members are key regulatory elements of their catalytic activities. Biochemical, structural, and cellular analyses have revealed that the linkers can lock the HECT domain in an inactive conformation and block the proposed allosteric ubiquitin binding site. Such linker-mediated autoinhibition of the HECT domain can be relieved by linker post-translational modifications, but complete removal of the brake can induce hyperactive autoubiquitination and E3 self destruction. These results clarify the mechanisms of several HECT protein cancer associated mutations and provide a new framework for understanding how HECT ubiquitin ligases must be finely tuned to ensure normal cellular behavior.

PubMed: 28475870
DOI: 10.1016/j.molcel.2017.03.020

Experimental method

X-RAY DIFFRACTION (2.3 Å)