Key result
Binding of human La protein to HCV domain IV requires the La motif and RRM1 to work in concert with the atypical RRM2 to recognize structural features of the RNA.
The study reveals a novel, structure-based mode of RNA recognition by the human La protein involving RRM2, which is crucial for understanding its role in viral translation initiation.
May inform La-targeted antiviral strategies for HCV; leaves open validation beyond this animal model.
Human La protein is an essential factor in the biology of both coding and non-coding RNAs. In the nucleus, La binds primarily to 3' oligoU containing RNAs, while in the cytoplasm La interacts with an array of different mRNAs lacking a 3' UUU(OH) trailer. An example of the latter is the binding of La to the IRES domain IV of the hepatitis C virus (HCV) RNA, which is associated with viral translation stimulation. By systematic biophysical investigations, we have found that La binds to domain IV using an RNA recognition that is quite distinct from its mode of binding to RNAs with a 3' UUU(OH) trailer: although the La motif and first RNA recognition motif (RRM1) are sufficient for high-affinity binding to 3' oligoU, recognition of HCV domain IV requires the La motif and RRM1 to work in concert with the atypical RRM2 which has not previously been shown to have a significant role in RNA binding. This new mode of binding does not appear sequence specific, but recognizes structural features of the RNA, in particular a double-stranded stem flanked by single-stranded extensions. These findings pave the way for a better understanding of the role of La in viral translation initiation.
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Martino et al. (2011) studied Hepatitis C virus (HCV) RNA interaction. La protein binding to HCV domain IV vs. La protein binding to 3' oligoU containing RNAs was evaluated on RNA recognition mode. Binding of human La protein to HCV domain IV requires the La motif and RRM1 to work in concert with the atypical RRM2 to recognize structural features of the RNA.
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