NMR Detection of Structures in the HIV-1 5'-Leader RNA That Regulate Genome Packaging

• Published in: Science (American Association for the Advancement of Science) Vol. 334; no. 6053; pp. 242 - 245
• Main Authors: Lu, Kun, Heng, Xiao, Garyu, Lianko, Monti, Sarah, Garcia, Eric L., Kharytonchyk, Siarhei, Dorjsuren, Bilguujin, Kulandaivel, Gowry, Jones, Simonne, Hiremath, Atheeth, Divakaruni, Sai Sachin, LaCotti, Courtney, Barton, Shawn, Tummillo, Daniel, Hosic, Azra, Edme, Kedy, Albrecht, Sara, Telesnitsky, Alice, Summers, Michael F.
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 14.10.2011; The American Association for the Advancement of Science
• Subjects: 5' Untranslated Regions; Base Pairing; Base pairs; Binding Sites; Biological and medical sciences; Chemical bases; Coding; Codon, Initiator; Dimerization; Dimers; Fundamental and applied biological sciences. Psychology; gag Gene Products, Human Immunodeficiency Virus - metabolism; Gene expression regulation; Genes, gag; Genetic mutation; Genome, Viral; Genomes; HIV; HIV-1 - genetics; HIV-1 - physiology; Human immunodeficiency virus; Human immunodeficiency virus 1; Human Immunodeficiency Virus Proteins - metabolism; Leaders; Microbiology; Monomers; Mutagenesis, Site-Directed; NMR; Nuclear magnetic resonance; Nuclear Magnetic Resonance, Biomolecular; Nucleic Acid Conformation; Nucleocapsid Proteins - metabolism; Packaging; Protein Binding; Protein Biosynthesis; Proteins; Replicative cycle, interference, host-virus relations, pathogenicity, miscellaneous strains; Ribonucleic acid; RNA; RNA, Viral - chemistry; RNA, Viral - genetics; Structural Elements (Construction); Translation; Virology; Virus Assembly; Virus; 5' terminal-Sequence; Encapsidation; Regulation(control); Leader sequence; RNA; Retroviridae; Human immunodeficiency virus; Detection; Genome; Lentivirus
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.1210460

The 5′-leader of the HIV-1 genome regulates multiple functions during viral replication via mechanisms that have yet to be established. We developed a nuclear magnetic resonance approach that enabled direct detection of structural elements within the intact leader (712-nucleotide dimer) that are critical for genome packaging. Residues spanning the gag start codon (AUG) form a hairpin in the monomeric leader and base pair with residues of the unique-5′ region (U5) in the dimer. U5:AUG formation promotes dimerization by displacing and exposing a dimer-promoting hairpin and enhances binding by the nucleocapsid (NC) protein, which is the cognate domain of the viral Gag polyprotein that directs packaging. Our findings support a packaging mechanism in which translation, dimerization, NC binding, and packaging are regulated by a common RNA structural switch.