STRUCTURAL BASIS OF THE RNA-BINDING SPECIFICITY OF HUMAN U1A PROTEIN

The RNP domain is a very common eukaryotic protein domain involved in recognition of a wide range of RNA structures and sequences, Two struc tures of human U1A in complex with distinct RNA substrates have reveal ed important aspects of RNP-RNA recognition, but have also raised intr iguing questions concerning the origin of binding specificity. The bet a-sheet of the domain provides an extensive RNA-binding platform for p acking aromatic RNA bases and hydrophobic protein side chains, However , many interactions between functional groups on the single-stranded n ucleotides and residues on the beta-sheet surface are potentially comm on to RNP proteins with diverse specificity and therefore make only li mited contribution to molecular discrimination. The refined structure of the U1A complex with the RNA polyadenylation inhibition element rep orted here clarifies the role of the RNP domain principal specificity determinants (the variable loops) in molecular recognition, The most v ariable region of RNP proteins, loop 3, plays a crucial role in defini ng the global geometry of the intermolecular interface, Electrostatic interactions with the RNA phosphodiester backbone involve protein side chains that are unique to U1A and are likely to be important for disc rimination. This analysis provides a novel picture of RNA-protein reco gnition, much closer to our current understanding of protein-protein r ecognition than that of DNA-protein recognition.