NEDD4L intramolecular interactions regulate its auto and substrate Na_V1.5 ubiquitination.

ABSTRACT: NEDD4L is a HECT-type E3 ligase that catalyzes the addition of ubiquitin to intracellular substrates such as the cardiac voltage-gated sodium channel, Na_V1.5. The intramolecular interactions of NEDD4L regulate its enzymatic activity which is essential for proteostasis. For Na_V1.5, this process is critical as alterations in Na⁺ current is involved in cardiac diseases including arrhythmias and heart failure. In this study, we perform extensive biochemical and functional analyses that implicate the C2 domain and the first WW-linker (1,2-linker) in the autoregulatory mechanism of NEDD4L. Through in vitro and electrophysiological experiments, the NEDD4L 1,2-linker was determined to be important in substrate ubiquitination of Na_V1.5. We establish the p

SUBMITTER: Wright KM 

PROVIDER: S-EPMC10933555 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature