Abstract
Influenza A is a negative sense RNA virus that kills hundreds of thousands of humans each year. Base pairing in RNA is very favorable, but possibilities for RNA secondary structure of the influenza genomic RNA have not been investigated. This work presents the first experimentally-derived exploration of potential secondary structure in an influenza A naked (protein-free) genomic segment. Favorable folding regions are revealed by in vitro chemical structure mapping, thermodynamics, bioinformatics, and binding to isoenergetic microarrays of an entire natural sequence of the 875 nt segment 8 vRNA and of a smaller fragment. Segment 8 has thermodynamically stable and evolutionarily conserved RNA structure and encodes essential viral proteins NEP and NS1. This suggests that vRNA self-folding may generate helixes and loops that are important at one or more stages of the influenza life cycle.
Highlights
Influenza A virus causes yearly epidemics that kill hundreds of thousands of humans [1] and undergoes genetic reassortments, that produce infrequent, but more deadly pandemics [2]
Genomic RNAs share a common organization consisting of a central open reading frame flanked on both ends by short (19–58 nt) untranslated regions (UTRs) [5]
Dimethyl sulfate (DMS) modification analysis was equivalent to that described above. For both SHAPE and DMS, at least three datasets were obtained from each primer and the average of results was used in the RNAstructure5.3 program [48, 49] for prediction of secondary structure (S1 Dataset)
Summary
Influenza A virus causes yearly epidemics that kill hundreds of thousands of humans [1] and undergoes genetic reassortments, that produce infrequent, but more deadly pandemics [2]. Influenza is a negative sense (-)RNA virus with a segmented genome. The genomic RNA orchestrates various functions including replication, transcription, translation, and virion assembly. Despite influenza genomic RNA importance, knowledge of its structure is limited. Genomic RNAs (vRNA) share a common organization consisting of a central open reading frame (antisense) flanked on both ends by short (19–58 nt) untranslated regions (UTRs) [5]. The base paired 5' and 3' ends form a structure called panhandle that is recognized by the viral polymerase complex [6]. Binding of polymerase induces a partial conformational change in the RNA structure [7, 8], thought to allow promoter activity and synthesis of viral mRNA utilizing an unusual host “cap-snatching” endonuclease activity [9].
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