One, Two, Three, Four! How Multiple RRMs Read the Genome Sequence

RRM-containing proteins are involved in most of the RNA metabolism steps. Their functions are closely related to their mode of RNA recognition, which has been studied by structural biologists for more than 20 years. In this chapter, we report on high-resolution structures of single and multi RRM-RNA complexes to explain the numerous strategies used by these domains to interact specifically with a large repertoire of RNA sequences. We show that multiple variations of their canonical fold can be used to adapt to different single-stranded sequences with a large range of affinities. Furthermore, we describe the consequences on RNA binding of the different structural arrangements found in tandem RRMs and higher order RNPs. Importantly, these structures also reveal with very high accuracy the RNA motifs bound specifically by RRM-containing proteins, which correspond very often to consensus sequences identified with genome-wide approaches. Finally, we show how structural and cellular biology can benefit from each other and pave a way for understanding, defining, and predicting a code of RNA recognition by the RRMs.