Catalysis of mRNA Capping with GDP Polyribonucleotidyltransferase Activity of Rabies Virus L Protein

Rabies virus (RABV) causes a lethal neurological disease in humans, posing threats to human health particularly in developing countries. RABV possesses a nonsegmented negative-strand (NNS) RNA genome, which is transcribed and replicated by a viral RNA-dependent RNA polymerase (RdRp) complex composed of a catalytic large (L) protein and its co-factor phospho-(P) protein in host cells. The L protein co-transcriptionally modifies viral pre-mRNAs into mature mRNAs to imitate higher eukaryotic mRNAs with the 5′-cap 1 structure and 3′-poly(A) tail. Our studies revealed that the mechanism of pre-mRNA capping by a GDP polyribonucleotidyltransferase (PRNTase) domain of the RABV L protein is fundamentally different from that by eukaryotic mRNA capping enzyme. Furthermore, a unique structural element, named the “priming-capping loop”, in the PRNTase domain was recently found to be required for transcription initiation as well as pre-mRNA capping. Thus, the virus-specific PRNTase domain represents a potential target for developing anti-RABV agents. This chapter focuses on the catalytic and regulatory roles of the RABV PRNTase domain in viral RNA biosynthesis.