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

Publication date: Available online 7 December 2018Source: Progress in Biophysics and Molecular BiologyAuthor(s): Shagufta Shafique, Sajid RashidAbstractRenal 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 pVHLWT, pVHLY98H, pVHLY112H, pVHLL118P and pVHLR167W 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 pVHLL118P 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 pVH...
Source: Progress in Biophysics and Molecular Biology - Category: Molecular Biology Source Type: research