%0 Journal Article
%T TRIAD3/RNF216 E3 ligase specifically synthesises K63-linked ubiquitin chains and is inactivated by mutations associated with Gordon Holmes syndrome
%J -
%D 2019
%R https://doi.org/10.1038/s41420-019-0158-6
%X TRIAD3/RNF216 is a ubiquitin ligase of the RING-in-between-RING family. Recent publications identified TRIAD3 mutations in patients with neurological diseases, including Gordon Holmes syndrome and Huntington-like disorder. To understand the functional relevance of these disease-associated mutations, we have tested the ubiquitin ligase activity of mutated TRIAD3 in vitro. Several of these point mutations completely abrogated TRIAD3¡¯s catalytic activity. Using mass spectrometry, we identified new TRIAD3-interacting proteins/substrates from mouse brain lysate, which provide a new link between TRIAD3 and processes involving clathrin-mediated endocytosis. Strikingly, we found that TRIAD3 synthesises specifically lysine-63 (K63)-linked poly-ubiquitin chains in vitro, a chain type that usually plays a role in mediating signalling events rather than triggering proteasomal degradation. Therefore, this finding is of great importance to further understand TRIAD3¡¯s cellular role and loss-of-function in disease
%U https://www.nature.com/articles/s41420-019-0158-6