Biochemistry & Molecular Pharmacology, University of Massachusetts Medical School
Abstract: RNA molecules, essential to numerous fundamental processes in cell biology, are
regulated by a wide variety of proteins through direct protein-RNA interactions. In this
study, we focus on a common RNA-binding domain organization that contains CCCH zinc
fingers organized in tandem zinc fingers (TZFs). TZF domains are found in many proteins
that specifically regulate the essential processes of post-transcriptional gene expression
and splicing. This seminar focuses on two human proteins (TTP and TIS11d) and two C.
elegans proteins (MEX-5 and POS-1). Although characterized by high sequence
homology, we have observed that these TZF domains recognize distinct RNA sequences
with high affinity and have differential folding propensities. We have identified the residues
that determine the folding propensity of the RNA-binding domain in the apo state and have
determined the mechanism through which they control folding. We have also demonstrated
that increased disorder of the RNA-binding domain is associated with differences in RNAbinding
activity in vitro and decreased activity in the cell.