Structural Basis for Importin-α Binding of the Human Immunodeficiency Virus Tat

Abstract HIV-1 has caused 35 million deaths globally, and approximately the same number is currently living with HIV-1. The trans-activator of transcription (Tat) protein of HIV-1 plays an important regulatory function in the virus life cycle, responsible for regulating the reverse transcription of...

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Autores principales:	K. M. Smith, Z. Himiari, S. Tsimbalyuk, J. K. Forwood
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/616e115463ca4f5ca45f13b157494d18
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spelling	oai:doaj.org-article:616e115463ca4f5ca45f13b157494d182021-12-02T11:52:19ZStructural Basis for Importin-α Binding of the Human Immunodeficiency Virus Tat10.1038/s41598-017-01853-72045-2322https://doaj.org/article/616e115463ca4f5ca45f13b157494d182017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01853-7https://doaj.org/toc/2045-2322Abstract HIV-1 has caused 35 million deaths globally, and approximately the same number is currently living with HIV-1. The trans-activator of transcription (Tat) protein of HIV-1 plays an important regulatory function in the virus life cycle, responsible for regulating the reverse transcription of the viral genome RNA. Tat is found in the nucleus of infected cells, but can also invade uninfected neighbouring cells. Regions within Tat responsible for these cellular localisations are overlapping and include a nuclear localisation signal (NLS) spanning 48GRKKRR, and a cell penetrating peptide (CPP) signal spanning 48GRKKRRQRRRAPQN. However, the mechanism by which this NLS/CPP region mediates interaction with the nuclear import receptors remains to be resolved structurally. Here, we establish that the HIV-1 Tat:NLS/CPP is able to form a stable and direct interaction with the classical nuclear import receptor importin-α and using x-ray crystallography, we have determined the molecular interface and binding determinants to a resolution of 2.0 Å. We show for the first time that the interface is the same as host factors such as Ku70 and Ku80, rather than other virus proteins such as Ebola VP24 that bind on the outer surface of importin-α.K. M. SmithZ. HimiariS. TsimbalyukJ. K. ForwoodNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q K. M. Smith Z. Himiari S. Tsimbalyuk J. K. Forwood Structural Basis for Importin-α Binding of the Human Immunodeficiency Virus Tat
description	Abstract HIV-1 has caused 35 million deaths globally, and approximately the same number is currently living with HIV-1. The trans-activator of transcription (Tat) protein of HIV-1 plays an important regulatory function in the virus life cycle, responsible for regulating the reverse transcription of the viral genome RNA. Tat is found in the nucleus of infected cells, but can also invade uninfected neighbouring cells. Regions within Tat responsible for these cellular localisations are overlapping and include a nuclear localisation signal (NLS) spanning 48GRKKRR, and a cell penetrating peptide (CPP) signal spanning 48GRKKRRQRRRAPQN. However, the mechanism by which this NLS/CPP region mediates interaction with the nuclear import receptors remains to be resolved structurally. Here, we establish that the HIV-1 Tat:NLS/CPP is able to form a stable and direct interaction with the classical nuclear import receptor importin-α and using x-ray crystallography, we have determined the molecular interface and binding determinants to a resolution of 2.0 Å. We show for the first time that the interface is the same as host factors such as Ku70 and Ku80, rather than other virus proteins such as Ebola VP24 that bind on the outer surface of importin-α.
format	article
author	K. M. Smith Z. Himiari S. Tsimbalyuk J. K. Forwood
author_facet	K. M. Smith Z. Himiari S. Tsimbalyuk J. K. Forwood
author_sort	K. M. Smith
title	Structural Basis for Importin-α Binding of the Human Immunodeficiency Virus Tat
title_short	Structural Basis for Importin-α Binding of the Human Immunodeficiency Virus Tat
title_full	Structural Basis for Importin-α Binding of the Human Immunodeficiency Virus Tat
title_fullStr	Structural Basis for Importin-α Binding of the Human Immunodeficiency Virus Tat
title_full_unstemmed	Structural Basis for Importin-α Binding of the Human Immunodeficiency Virus Tat
title_sort	structural basis for importin-α binding of the human immunodeficiency virus tat
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/616e115463ca4f5ca45f13b157494d18
work_keys_str_mv	AT kmsmith structuralbasisforimportinabindingofthehumanimmunodeficiencyvirustat AT zhimiari structuralbasisforimportinabindingofthehumanimmunodeficiencyvirustat AT stsimbalyuk structuralbasisforimportinabindingofthehumanimmunodeficiencyvirustat AT jkforwood structuralbasisforimportinabindingofthehumanimmunodeficiencyvirustat
_version_	1718395106484027392

Structural Basis for Importin-α Binding of the Human Immunodeficiency Virus Tat

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