Structural and Functional Divergence of MEX-3 KH Domains Dictates RNA Binding and Identifies MEX3A/C as Pan-Cancer Prognostic Markers

Abstract

In recent years, RNA-binding proteins (RBPs) have emerged as key regulators of post-transcriptional processes, embryonic development, and cancer cell proliferation. The MEX-3 family consists of evolutionarily conserved RBPs that have roles in post-transcriptional expression, embryonic development, and cancer processes. These proteins are distinguished by their structural features, notably the tandem KH domains (KH1 and KH2) and a C-terminal RING-like domain. Structure analysis revealed specific functional specialization of the KH domains, where the GxxG loop of the KH1 domain supports linear RNA binding and the extended GxxxGxxG loop of the KH2 domain supports complex RNA conformations. Through pan-cancer bioinformatics analysis, we found strong correlations of MEX-3 gene expressions, patient outcomes, and immune cell infiltration in different types of cancer, implicating specifically MEX3A and MEX3C as cancer prognostic markers and targets of therapy. While our study provides valuable insights into the molecular mechanisms of MEX-3 proteins, experimental validation including the enrichment analyses and protein-protein interaction mapping will need to establish these bioinformatics predictions conclusively. Overall, this study provides a solid foundation of the MEX-3 proteins' multifunctional character and emphasizes their potential in cancer therapy and prognosis.