Dr. Mike Summers
UNIVERSITY OF MARYLAND, BALTIMORE COUNTY
Department of Chemistry and Biochemistry
September 18, 2020
“Structural Basis for Transcriptional Control of HIV-1 RNA Fate“
Heterogeneous transcriptional start site usage by HIV-1 produces 5′-capped RNAs beginning with one, two, or three 5′-guanosines (Cap1G, Cap2G, Cap3G, respectively) that are either selected for packaging as genomes (Cap1G) or retained in cells as translatable mRNAs (Cap2G/Cap3G). To understand how 5′-guanosine number influences fate, we probed the structures of capped HIV-1 leader RNAs by 2H-edited NMR. The Cap1G transcript adopts a dimeric multi-hairpin structure that sequesters the cap, inhibits interactions with translation initiation factor eIF4E, and resists decapping. The Cap2G/Cap3G transcripts adopt an alternate structure with an elongated central helix, exposed splice donor residues, and an accessible cap. Extensive remodeling, achieved at the energetic cost of a G-C base pair, explains how a single 5′ guanosine modifies the function of a ~9 kilobase HIV-1 transcript.