Structural basis for renal cancer by the dynamics of pVHL-dependent JADE1 stabilization and β-catenin regulation

Renal cancer is the major cause of mortality due to abnormal functioning of von Hippel-Lindau (pVHL) and Jade Family PHD Finger 1 (JADE1) complex. E3 ubiquitin ligase JADE1 is stabilized by pVHL interaction through its plant homeodomains (PHDs). JADE1 acts as a renal tumor suppressor that promotes the ubiquitination and degradation of β-catenin by inhibiting canonical WNT signalling. Current study focuses on the structural characterization of reported missense mutations in pVHL through in silico approaches. The predicted 3-dimensional structures of pVHL^WT, pVHL^Y98H, pVHL^Y112H, pVHL^L118P and pVHL^R167W were subjected to binding analysis against JADE1 through molecular docking and simulation assays. In all cases, JADE1 binding was observed at the β-domain, except pVHL^L118P that exhibited binding with JADE1 through its α-domain. Our results signify that JADE1 stabilization is induced by pVHL α-domain, while β-domain is required for JADE1 binding. pVHL binding was mediated through β1 and β2-strands against the concave surface of the JADE1-PHD domain. The pVHL-JADE1 complex was evaluated to scrutinize the β-catenin-binding interface, which suggested the contribution of both α and β-domains of pVHL in β-catenin binding. The eleven-residue (Tyr30-Thr40) β-catenin segment exhibited association in a bipartite manner with pVHL-JADE1 complex. The presented model depicts a pVHL-JADE1 interface for the cooperative regulation of β-catenin binding. We propose that reduced JADE1 stabilization in case of pVHL^L118P and pVHL^R167W may correlate with the increased activity of β-catenin that may lead to renal cancer through β-catenin de-repression. Overall, β-catenin targeting mechanism coupled with the structural knowledge of JADE1-pVHL complex will provide better understanding of renal cancer pathogenesis.