Structural basis for transcriptional start site control of HIV-1 RNA fate.
Joshua D BrownSiarhei KharytonchykIssac ChaudryAishwarya S IyerHannah CarterGhazal BeckerYash DesaiLindsay GlangSeung H ChoiKarndeep SinghMichael W LoprestiMatthew OrellanaTatiana RodriguezUbiomo ObohJana HijjiFrances Grace GhingerKailan StewartDillion FrancisBryce EdwardsPatrick ChenDavid A CaseAlice TelesnitskyMichael F SummersPublished in: Science (New York, N.Y.) (2020)
Heterogeneous transcriptional start site usage by HIV-1 produces 5'-capped RNAs beginning with one, two, or three 5'-guanosines (Cap1G, Cap2G, or Cap3G, respectively) that are either selected for packaging as genomes (Cap1G) or retained in cells as translatable messenger RNAs (mRNAs) (Cap2G and Cap3G). To understand how 5'-guanosine number influences fate, we probed the structures of capped HIV-1 leader RNAs by deuterium-edited nuclear magnetic resonance. The Cap1G transcript adopts a dimeric multihairpin structure that sequesters the cap, inhibits interactions with eukaryotic translation initiation factor 4E, and resists decapping. The Cap2G and 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.
Keyphrases
- antiretroviral therapy
- hiv infected
- hiv positive
- human immunodeficiency virus
- hiv testing
- magnetic resonance
- hiv aids
- hepatitis c virus
- men who have sex with men
- transcription factor
- oxidative stress
- structural basis
- computed tomography
- crispr cas
- rna seq
- molecular dynamics simulations
- signaling pathway
- cell cycle arrest
- pi k akt