Molecular dynamics and structural analysis of the binding of COP1 E3 ubiquitin ligase to β‐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 β‐catenin expression. The interaction mechanism between COP1 E3 ligase and β‐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 β‐catenin and COP1. Here, through in silico approaches, we ascribe the COP1 binding pattern against TRIBs and β‐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 β‐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 β‐catenin phosphodegron signature for binding to WD40 domain of COP1. Thorough understanding of the structural basis for TRIB‐mediated regulation of WNT/β‐catenin signaling may help in devising more promising therapeutic strategy for liver and colorectal cancers. [ABSTRACT FROM AUTHOR]