In Silico Structural Modeling of the HuR-mRNA Complex: Insights into Structural and Functional Regulation.

The RNA-binding protein HuR (embryonic lethal abnormal vision-like protein 1) regulates mRNA stability and translation. HuR contains three RNA-recognition motifs (RRMs): the RRM1 and RRM2 confer high-affinity mRNA binding, while RRM3 mediates protein oligomerization. Although HuR is predominantly nuclear, cellular stimuli trigger its cytoplasmic translocation via a nucleocytoplasmic shuttling sequence between the RRM2 and RRM3 domains. Despite HuR's critical role in post-transcriptional gene regulation, its full-length three-dimensional (3D) structure remains uncharacterized. In this study, we employed an in silico approach, combining molecular modeling, atomistic, and coarse-grained molecular dynamics simulations to build and validate a 3D model of the full-length HuR in complex with an mRNA fragment. Structural analysis of the model identified a tyrosine residue as a key mediator of HuR-RNA interaction stability and provided novel structural insights into HuR's RNA-binding mechanism, contributing to a deeper understanding of its regulatory functions.