Regulatory mechanisms of Nedd4-like E3 ubiquitin ligases

Nedd4-2 is a HECT E3 ligase that plays a key role in pathophysiology by regulating multiple substrates. Nedd4-2 dysregulation leads to respiratory distress, hypertension, electrolyte imbalance, and kidney disease. Nedd4-2 is regulated via phosphorylation and binding to various protein partners (14-3-3 proteins, arrestins, ClC5). Our goal is to elucidate the regulatory mechanism of various HECT E3 ligases (Nedd4L, Smurf1, Rsp5) to understand the role protein-protein interactions in their regulation.

Molecular basis of apoptosis signal-regulating kinase 1 (ASK1) regulation

ASK1 is a MAP3K kinase that controls various responses to oxidative and ER stress and Ca influx via p38 and JNK signaling pathways. Dysregulation of ASK1 activity is connected to many diseases: neurological disorders, ALS, cardiovascular disease, diabetes and cancer. We aim to elucidate the molecular basis of ASK1 regulation and to understand the role of ASK1 binding partners (TRX, TRAF, 14-3-3 proteins) in its regulation using integrative structural biology methods (cryo-EM, SAXS etc.).