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Phosphomimetic S207D Lysyl–tRNA Synthetase Binds HIV-1 5′UTR in an Open Conformation and Increases RNA Dynamics
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Phosphomimetic S207D Lysyl–tRNA Synthetase Binds HIV-1 5′UTR in an Open Conformation and Increases RNA Dynamics
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Journal Article
Phosphomimetic S207D Lysyl–tRNA Synthetase Binds HIV-1 5′UTR in an Open Conformation and Increases RNA Dynamics
2022
Overview
Interactions between lysyl–tRNA synthetase (LysRS) and HIV-1 Gag facilitate selective packaging of the HIV-1 reverse transcription primer, tRNALys3. During HIV-1 infection, LysRS is phosphorylated at S207, released from a multi-aminoacyl–tRNA synthetase complex and packaged into progeny virions. LysRS is critical for proper targeting of tRNALys3 to the primer-binding site (PBS) by specifically binding a PBS-adjacent tRNA-like element (TLE), which promotes release of the tRNA proximal to the PBS. However, whether LysRS phosphorylation plays a role in this process remains unknown. Here, we used a combination of binding assays, RNA chemical probing, and small-angle X-ray scattering to show that both wild-type (WT) and a phosphomimetic S207D LysRS mutant bind similarly to the HIV-1 genomic RNA (gRNA) 5′UTR via direct interactions with the TLE and stem loop 1 (SL1) and have a modest preference for binding dimeric gRNA. Unlike WT, S207D LysRS bound in an open conformation and increased the dynamics of both the PBS region and SL1. A new working model is proposed wherein a dimeric phosphorylated LysRS/tRNA complex binds to a gRNA dimer to facilitate tRNA primer release and placement onto the PBS. Future anti-viral strategies that prevent this host factor-gRNA interaction are envisioned.
Publisher
MDPI AG,MDPI
Subject
/ Analysis
/ genomics
/ gRNA
/ HIV
/ Human immunodeficiency virus
/ human immunodeficiency virus type 1
/ Ligand binding (Biochemistry)
/ mutants
/ Mutation
/ NMR
/ Plasmids
/ progeny
/ Proteins
/ RNA
/ selective 2′-hydroxyl acylation analyzed by primer extension
/ small-angle X-ray scattering
/ tRNA
/ Virions
