Structural basis for transcriptional start site control of HIV-1 RNA fate
Science, April 2020
Joshua D. Brown, Siarhei Kharytonchyk, Issac Chaudry, Aishwarya S. Iyer, Hannah Carter, Ghazal Becker, Yash Desai, Lindsay Glang, Seung H. Choi, Karndeep Singh, Michael W. Lopresti, Matthew Orellana, Tatiana Rodriguez, Ubiomo Oboh, Jana Hijji, Frances Grace Ghinger, Kailan Stewart, Dillion Francis, Bryce Edwards, Patrick Chen, David A. Case, Alice Telesnitsky, Michael F. Summers, Brown, Joshua D, Kharytonchyk, Siarhei, Chaudry, Issac, Iyer, Aishwarya S, Carter, Hannah, Becker, Ghazal, Desai, Yash, Glang, Lindsay, Choi, Seung H, Singh, Karndeep, Lopresti, Michael W, Orellana, Matthew, Rodriguez, Tatiana, Oboh, Ubiomo, Hijji, Jana, Ghinger, Frances Grace, Stewart, Kailan, Francis, Dillion, Edwards, Bryce, Chen, Patrick, Case, David A, Telesnitsky, Alice, Summers, Michael F
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.
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