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.

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