Mammalian and bacterial adaptors function as co-disinhibitory pairs to activate the E3 ubiquitin ligase WWP2.

ABSTRACT: The NEDD4-like E3 ubiquitin ligase, WWP2, is involved in a range of host processes from cell differentiation to T cell immunity. Ligase activity is tightly regulated, with WWP2 being held in an autoinhibited state. The binding of a PY motif-containing adaptor, an Ndfip, via the WW domains of NEDD4-like E3 ubiquitin ligases leads to their disinhibition. Here, we show that the canonical Ndfip, NDFIP2, requires multiple PY motifs for interaction with and activation of WWP2. In contrast, the single PY-motif containing Ndfips TMEM127 and SUSD6 functions as a co-disinhibitory pair. TMEM127 and the Salmonella protein SteD also function as a co-disinhibitory pair. However, SteD requires a different region of WWP2, the C2 domain, for interaction with WWP2, and this interaction results in disinhibit

SUBMITTER: Blundell SV 

PROVIDER: S-EPMC12720080 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature