Key result
Mutations in the Delta1 loop and template channel of the HCV RNA-dependent RNA polymerase altered de novo initiation and host protein interactions, suggesting a flexible locking mechanism.
The Delta1 loop of the HCV RdRp serves as a flexible locking mechanism regulating conformations needed for de novo initiation and elongative RNA synthesis.
Mutational analysis of the hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp) template channel identified two residues, Trp(397) and His(428), which are required for de novo initiation but not for extension from a primer. These two residues interact with the Delta1 loop on the surface of the RdRp. A deletion within the Delta1 loop also resulted in comparable activities. The mutant proteins exhibit increased double-stranded RNA binding compared with the wild type, suggesting that the Delta1 loop serves as a flexible locking mechanism to regulate the conformations needed for de novo initiation and for elongative RNA synthesis. A similar locking motif can be found in other viral RdRps. Products associated with the open conformation of the HCV RdRp were inhibited by interaction with the retinoblastoma protein but not cyclophilin A. Different conformations of the HCV RdRp can thus affect RNA synthesis and interaction with cellular proteins.
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Chinnaswamy et al. (2008) studied Hepatitis C virus (HCV). Mutational analysis of HCV RdRp template channel (Trp397, His428, Delta1 loop) vs. Wild type HCV RdRp was evaluated on RNA synthesis (de novo initiation and extension) and host protein interaction. Mutations in the Delta1 loop and template channel of the HCV RNA-dependent RNA polymerase altered de novo initiation and host protein interactions, suggesting a flexible locking mechanism.
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