Recognition of Nascent RNA by the Human La Antigen: Conserved and Divergent Features of Structure and Function

La is a conserved RNA-binding phosphoprotein that interacts with a large variety of ligands. The most ubiquitous function of La is association with newly synthesized RNA polymerase (Pol) III transcripts via their common UUU-OH 39 termini and stabilization of these against exonucleolytic digestion. Accumulating evidence also indicates an activity for La in internal ribosome entry site-mediated translation in mammalian cells and in the metabolism of a subset of 39-processed snRNA intermediates that end in uridylates but are synthesized by Pol II. The most highly conserved region of La resides in the N-terminal domain (NTD), and this appears to mediate highaffinity UUU-OH recognition. As critically reviewed here by comparison to a consensus core RNA recognition motif (RRM) structure, the NTD can be modeled into a pair of tandem RRMs. In addition to the conserved NTD, human La (hLa) protein contains a C-terminal domain (CTD) that harbors a third RRM and a potential Walker A motif that appears to recognize the 59-ppp ends of nascent RNAs. The resulting bipartite mode of RNA binding can account for previously unexplained observations and may underlie a unifying principle of La function. While a role for hLa in transcription remains controversial, its presence in a Pol III holoenzyme suggests a role reminiscent of the CTD of Pol II, as an integrator of transcriptional and posttranscriptional activities that include 59- and 39-RNA metabolism. Evidence that the 59-end-RNA recognition activity of hLa can be modulated by phosphorylation provides mechanistic insight into the signal transduction