Intrinsically Disordered Regions Facilitate Mlp1-Nab2 Recognition in mRNA Quality Control

Quality control of messenger RNAs (mRNAs) is an essential step in mRNA biogenesis, ensuring that only properly processed transcripts are exported from the nucleus. Myosin-like protein 1 (Mlp1), a nuclear basket protein, plays a central role in this process by interacting with RNA-binding proteins (RBPs), including Nab2. While previous studies identified Phe73 in Nab2 as critical for Mlp1 binding, the molecular mechanism has remained unclear. Here, we employed an integrated computational strategy combining protein structure prediction, docking, and molecular dynamics simulations to develop a mechanistic model of the Mlp1-Nab2 interaction. Our results suggest that Phe73 does not act through direct contacts with Mlp1, but instead stabilizes intramolecular interactions between Nab2 helices that promote a compact conformation. This conformational stabilization is compatible with stronger association with the flexible C-terminal domain of Mlp1. Mutation of Phe73 to alanine disrupted this helix–helix stabilization and weakened binding, whereas substitution with tryptophan preserved and enhanced the interaction, consistent with prior experimental findings. Additional mutations of hydrophobic residues on the adjacent Nab2 helix (I87, I91, M94) further supported their role in mediating complex stability. Together, our findings provide computational insights into a plausible binding mechanism for the Mlp1-Nab2 interaction, in which the structural flexibility of Mlp1’s disordered domain enables adaptive recognition of Nab2. This mechanism may represent a general strategy by which the nuclear basket accommodates and inspects diverse mRNPs, highlighting the importance of flexible protein–protein recognition in mRNA quality control.