Molecular dynamics and structural analysis of the binding of COP1 E3 ubiquitin ligase to beta-catenin and TRIB pseudokinases

Tribbles pseudokinases, Tribbles homolog 1 (TRIB1), Tribbles homolog 2 (TRIB2), and Tribbles homolog 3 (TRIB3), bind to constitutive photomorphogenesis protein 1 (COP1) E3 ligase to mediate the regulation of beta-catenin expression. The interaction mechanism between COP1 E3 ligase and beta-catenin has not been addressed to date. Based on the functional presence of TRIBs in wingless-related integration site (WNT) signaling, we analyzed their interaction patterns with beta-catenin and COP1. Here, through in silico approaches, we ascribe the COP1 binding pattern against TRIBs and beta-catenin. TRIB1 (355-DQIVPEY-361), TRIB2 (326-DQLVPDV-332), and TRIB3 (333-AQVVPDG-339) peptides revealed a shallow binding pocket at the COP1 interface to accommodate the V-P sequence motif. Reinvigoration of the comparative binding pattern and subtle structural analysis via docking, molecular dynamics simulations, molecular mechanics Poisson-Boltzmann surface area, topological, and tunnel analysis revealed that both beta-catenin phosphodegron (DSGXXS) and TRIB (D/E/AQXVPD/E) motifs occupied a common COP1 binding site. Current study suggests a structural paradigm of TRIB homologs bearing a conserved motif that may compete with beta-catenin phosphodegron signature for binding to WD40 domain of COP1. Thorough understanding of the structural basis for TRIB-mediated regulation of WNT/beta-catenin signaling may help in devising more promising therapeutic strategy for liver and colorectal cancers.