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How HIV-1 Integrase Associates with Human Mitochondrial Lysyl-tRNA Synthetase
Replication of human immunodeficiency virus type 1 (HIV-1) requires the packaging of tRNA(Lys,3) from the host cell into the new viral particles. The GagPol viral polyprotein precursor associates with mitochondrial lysyl-tRNA synthetase (mLysRS) in a complex with tRNA(Lys), an essential step to init...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589778/ https://www.ncbi.nlm.nih.gov/pubmed/33096929 http://dx.doi.org/10.3390/v12101202 |
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author | Phongsavanh, Xaysongkhame Al-Qatabi, Noha Shaban, Mohammed Samer Khoder-Agha, Fawzi El Asri, Merwan Comisso, Martine Guérois, Raphaël Mirande, Marc |
author_facet | Phongsavanh, Xaysongkhame Al-Qatabi, Noha Shaban, Mohammed Samer Khoder-Agha, Fawzi El Asri, Merwan Comisso, Martine Guérois, Raphaël Mirande, Marc |
author_sort | Phongsavanh, Xaysongkhame |
collection | PubMed |
description | Replication of human immunodeficiency virus type 1 (HIV-1) requires the packaging of tRNA(Lys,3) from the host cell into the new viral particles. The GagPol viral polyprotein precursor associates with mitochondrial lysyl-tRNA synthetase (mLysRS) in a complex with tRNA(Lys), an essential step to initiate reverse transcription in the virions. The C-terminal integrase moiety of GagPol is essential for its association with mLysRS. We show that integrases from HIV-1 and HIV-2 bind mLysRS with the same efficiency. In this work, we have undertaken to probe the three-dimensional (3D) architecture of the complex of integrase with mLysRS. We first established that the C-terminal domain (CTD) of integrase is the major interacting domain with mLysRS. Using the pBpa-photo crosslinking approach, inter-protein cross-links were observed involving amino acid residues located at the surface of the catalytic domain of mLysRS and of the CTD of integrase. In parallel, using molecular docking simulation, a single structural model of complex was found to outscore other alternative conformations. Consistent with crosslinking experiments, this structural model was further probed experimentally. Five compensatory mutations in the two partners were successfully designed which supports the validity of the model. The complex highlights that binding of integrase could stabilize the tRNA(Lys):mLysRS interaction. |
format | Online Article Text |
id | pubmed-7589778 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-75897782020-10-29 How HIV-1 Integrase Associates with Human Mitochondrial Lysyl-tRNA Synthetase Phongsavanh, Xaysongkhame Al-Qatabi, Noha Shaban, Mohammed Samer Khoder-Agha, Fawzi El Asri, Merwan Comisso, Martine Guérois, Raphaël Mirande, Marc Viruses Article Replication of human immunodeficiency virus type 1 (HIV-1) requires the packaging of tRNA(Lys,3) from the host cell into the new viral particles. The GagPol viral polyprotein precursor associates with mitochondrial lysyl-tRNA synthetase (mLysRS) in a complex with tRNA(Lys), an essential step to initiate reverse transcription in the virions. The C-terminal integrase moiety of GagPol is essential for its association with mLysRS. We show that integrases from HIV-1 and HIV-2 bind mLysRS with the same efficiency. In this work, we have undertaken to probe the three-dimensional (3D) architecture of the complex of integrase with mLysRS. We first established that the C-terminal domain (CTD) of integrase is the major interacting domain with mLysRS. Using the pBpa-photo crosslinking approach, inter-protein cross-links were observed involving amino acid residues located at the surface of the catalytic domain of mLysRS and of the CTD of integrase. In parallel, using molecular docking simulation, a single structural model of complex was found to outscore other alternative conformations. Consistent with crosslinking experiments, this structural model was further probed experimentally. Five compensatory mutations in the two partners were successfully designed which supports the validity of the model. The complex highlights that binding of integrase could stabilize the tRNA(Lys):mLysRS interaction. MDPI 2020-10-21 /pmc/articles/PMC7589778/ /pubmed/33096929 http://dx.doi.org/10.3390/v12101202 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Phongsavanh, Xaysongkhame Al-Qatabi, Noha Shaban, Mohammed Samer Khoder-Agha, Fawzi El Asri, Merwan Comisso, Martine Guérois, Raphaël Mirande, Marc How HIV-1 Integrase Associates with Human Mitochondrial Lysyl-tRNA Synthetase |
title | How HIV-1 Integrase Associates with Human Mitochondrial Lysyl-tRNA Synthetase |
title_full | How HIV-1 Integrase Associates with Human Mitochondrial Lysyl-tRNA Synthetase |
title_fullStr | How HIV-1 Integrase Associates with Human Mitochondrial Lysyl-tRNA Synthetase |
title_full_unstemmed | How HIV-1 Integrase Associates with Human Mitochondrial Lysyl-tRNA Synthetase |
title_short | How HIV-1 Integrase Associates with Human Mitochondrial Lysyl-tRNA Synthetase |
title_sort | how hiv-1 integrase associates with human mitochondrial lysyl-trna synthetase |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589778/ https://www.ncbi.nlm.nih.gov/pubmed/33096929 http://dx.doi.org/10.3390/v12101202 |
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