期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 29, 期 4, 页码 306-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41594-022-00746-2
关键词
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资金
- Helmholtz Association [VH-NG-1347]
- Bundesministerium fur Bildung und Forschung [COMPLS-182]
- Peter und Traudl Engelhorn Stiftung
- European Research Council (ERC) [948636]
- European Research Council (ERC) [948636] Funding Source: European Research Council (ERC)
RNA dimerization plays a crucial role in the HIV-1 life cycle and genome packaging. Using FARS-seq, we identified important nucleotides and distinct structural conformations in the HIV-1 5' UTR that regulate the dimerization process. Our findings provide insights into the late stages of HIV-1 life cycle and unravel the mechanistic link between RNA dimerization, Pr55Gag binding, and genome packaging.
RNA dimerization is the noncovalent association of two human immunodeficiency virus-1 (HIV-1) genomes. It is a conserved step in the HIV-1 life cycle and assumed to be a prerequisite for binding to the viral structural protein Pr55(Gag) during genome packaging. Here, we developed functional analysis of RNA structure-sequencing (FARS-seq) to comprehensively identify sequences and structures within the HIV-1 5 ' untranslated region (UTR) that regulate this critical step. Using FARS-seq, we found nucleotides important for dimerization throughout the HIV-1 5 ' UTR and identified distinct structural conformations in monomeric and dimeric RNA. In the dimeric RNA, key functional domains, such as stem-loop 1 (SL1), polyadenylation signal (polyA) and primer binding site (PBS), folded into independent structural motifs. In the monomeric RNA, SL1 was reconfigured into long- and short-range base pairings with polyA and PBS, respectively. We show that these interactions disrupt genome packaging, and additionally show that the PBS-SL1 interaction unexpectedly couples the PBS with dimerization and Pr55(Gag) binding. Altogether, our data provide insights into late stages of HIV-1 life cycle and a mechanistic explanation for the link between RNA dimerization and packaging. Comprehensive functional and structural probing of the HIV-1 5 ' untranslated region reveals novel interactions that regulate RNA dimerization, Pr55Gag binding and genome packaging into virions.
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