Mechanistic insights into the HuR-V225I mutation and its impact on PKCδ binding dynamics in adult T-cell leukemia

HuR (ELAVL1) is a key RNA-binding protein involved in mRNA stability and translation, and its disrupted localization and function are strongly associated with leukemic development. This study investigates the interaction between HuR and the PKCδ kinase domain to determine the effects of PKCδ-mediated phosphorylation and the V225I mutation associated with leukemia on its interaction. Four molecular systems were modeled: wild-type HuR with unphosphorylated PKCδ (WT-UP), wild-type HUR with phosphorylated PKCδ (WT-P), mutant HuR (V225I) with unphosphorylated PKCδ (MT-UP), and mutant HuR (V225I) with phosphorylated PKCδ (MT-P). Through protein-protein docking and molecular dynamics simulations, we found that the WT-P and MT-UP complexes display strong binding and conformational stability, suggesting that both phosphorylation of wild-type HuR and the V225I mutation independently enhance the HuR-PKCδ interaction. However, interactions were reduced due to mutation and phosphorylation (MT-P), as evidenced by lower binding affinities, decreased interface stability, and increased conformational changes. It further indicates that these modifications can interfere rather than exert regulatory effects. These findings suggest that the V225I mutation may mimic and compete with phosphorylation, thereby influencing HuR's cytoplasmic accumulation and its role in mRNA stabilization, which is key to leukemogenesis. This comprehensive structural analysis advances our understanding of how genetic and post-translational modifications modulate HuR-PKCδ complexes and highlights molecular features of potential value for developing targets and innovative therapies for Adult T-cell leukemia.