RNA-Binding Domain Disorder Modulates the RNA Destabilizing Activity in the TTP Family of Proteins

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Despite the importance of RNA-binding proteins to gene regulation, our understanding of how their structure and dynamics contribute to their biological activity is limited. In this study, we focus on two related RNA-binding proteins—TTP and TIS11d—that regulate the stability of mRNA transcripts encoding key cancer-related proteins, such as tumor necrosis factor-α and vascular endothelial growth factor. These two proteins display differential folding propensity in the absence of RNA, despite sharing a high sequence identity. We identified three residues located at the C-terminal end of an α-helix that determine the folding propensity of the RNA-binding domain in the apo state. We also showed that stabilization of the structure of the RNA-binding domain is associated with differences in RNA-binding activity in vitro and increased RNA-destabilizing activity in the cell. Phylogenetic analysis indicates that this family of proteins has only recently evolved to be able to modulate its biological activity through its dynamic structure.