Covariance analysis of RNA recognition motifs identifies functionally linked amino acids

The RNA recognition motif (RRM) is one of the most common eukaryotic protei n motifs. RRM sequences form a conserved globular structure known as the RN A-binding domain (RBD) or the ribonucleoprotein domain. Many proteins that contain RRM sequences bind RNA in a sequence-specific manner. To investigat e the basis for the RNA-binding specificity of RRMs, we subjected 330 align ed RRM sequences to covariance analysis. The analysis revealed a single net work of covariant amino acid pairs comprising the buried core of the RED an d a surface patch. Structural studies have implicated a subset of these res idues in RNA binding. The covariance linkages identify a larger set of amin o acid residues, including some not directly in contact with bound RNA, tha t may influence RNA-binding specificity. (C) 2001 Academic Press.