INI1/SMARCB1 Rpt1 domain mimics TAR RNA in binding to integrase to facilitate HIV-1 replication

Updesh Dixit; Savita Bhutoria; Xuhong Wu; Liming Qiu; Menachem Spira; Sheeba Mathew; Richard Harris; Lucas J. Adams; Sean Cahill; Rajiv Pathak; P. Rajesh Kumar; Minh Nguyen; Seetharama A. Acharya; Michael Brenowitz; Steven C. Almo; Xiaoqin Zou; Alasdair C. Steven; David Cowburn; Mark Girvin; Ganjam V. Kalpana

doi:10.1038/s41467-021-22733-9

INI1/SMARCB1 Rpt1 domain mimics TAR RNA in binding to integrase to facilitate HIV-1 replication

Updesh Dixit, Savita Bhutoria, Xuhong Wu, Liming Qiu, Menachem Spira, Sheeba Mathew, Richard Harris, Lucas J. Adams, Sean Cahill, Rajiv Pathak, P. Rajesh Kumar, Minh Nguyen, Seetharama A. Acharya, Michael Brenowitz, Steven C. Almo, Xiaoqin Zou, Alasdair C. Steven, David Cowburn, Mark Girvin, Ganjam V. Kalpana

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

INI1/SMARCB1 binds to HIV-1 integrase (IN) through its Rpt1 domain and exhibits multifaceted role in HIV-1 replication. Determining the NMR structure of INI1-Rpt1 and modeling its interaction with the IN-C-terminal domain (IN-CTD) reveal that INI1-Rpt1/IN-CTD interface residues overlap with those required for IN/RNA interaction. Mutational analyses validate our model and indicate that the same IN residues are involved in both INI1 and RNA binding. INI1-Rpt1 and TAR RNA compete with each other for IN binding with similar IC₅₀ values. INI1-interaction-defective IN mutant viruses are impaired for incorporation of INI1 into virions and for particle morphogenesis. Computational modeling of IN-CTD/TAR complex indicates that the TAR interface phosphates overlap with negatively charged surface residues of INI1-Rpt1 in three-dimensional space, suggesting that INI1-Rpt1 domain structurally mimics TAR. This possible mimicry between INI1-Rpt1 and TAR explains the mechanism by which INI1/SMARCB1 influences HIV-1 late events and suggests additional strategies to inhibit HIV-1 replication.

Original language	English (US)
Article number	2743
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-22733-9
State	Published - Dec 1 2021

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-021-22733-9

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Dixit, U., Bhutoria, S., Wu, X., Qiu, L., Spira, M., Mathew, S., Harris, R., Adams, L. J., Cahill, S., Pathak, R., Rajesh Kumar, P., Nguyen, M., Acharya, S. A., Brenowitz, M., Almo, S. C., Zou, X., Steven, A. C., Cowburn, D., Girvin, M., & Kalpana, G. V. (2021). INI1/SMARCB1 Rpt1 domain mimics TAR RNA in binding to integrase to facilitate HIV-1 replication. Nature communications, 12(1), Article 2743. https://doi.org/10.1038/s41467-021-22733-9

Dixit, U, Bhutoria, S, Wu, X, Qiu, L, Spira, M, Mathew, S, Harris, R, Adams, LJ, Cahill, S , Pathak, R, Rajesh Kumar, P, Nguyen, M, Acharya, SA, Brenowitz, M , Almo, SC, Zou, X, Steven, AC, Cowburn, D, Girvin, M & Kalpana, GV 2021, 'INI1/SMARCB1 Rpt1 domain mimics TAR RNA in binding to integrase to facilitate HIV-1 replication', Nature communications, vol. 12, no. 1, 2743. https://doi.org/10.1038/s41467-021-22733-9

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title = "INI1/SMARCB1 Rpt1 domain mimics TAR RNA in binding to integrase to facilitate HIV-1 replication",

abstract = "INI1/SMARCB1 binds to HIV-1 integrase (IN) through its Rpt1 domain and exhibits multifaceted role in HIV-1 replication. Determining the NMR structure of INI1-Rpt1 and modeling its interaction with the IN-C-terminal domain (IN-CTD) reveal that INI1-Rpt1/IN-CTD interface residues overlap with those required for IN/RNA interaction. Mutational analyses validate our model and indicate that the same IN residues are involved in both INI1 and RNA binding. INI1-Rpt1 and TAR RNA compete with each other for IN binding with similar IC50 values. INI1-interaction-defective IN mutant viruses are impaired for incorporation of INI1 into virions and for particle morphogenesis. Computational modeling of IN-CTD/TAR complex indicates that the TAR interface phosphates overlap with negatively charged surface residues of INI1-Rpt1 in three-dimensional space, suggesting that INI1-Rpt1 domain structurally mimics TAR. This possible mimicry between INI1-Rpt1 and TAR explains the mechanism by which INI1/SMARCB1 influences HIV-1 late events and suggests additional strategies to inhibit HIV-1 replication.",

author = "Updesh Dixit and Savita Bhutoria and Xuhong Wu and Liming Qiu and Menachem Spira and Sheeba Mathew and Richard Harris and Adams, {Lucas J.} and Sean Cahill and Rajiv Pathak and {Rajesh Kumar}, P. and Minh Nguyen and Acharya, {Seetharama A.} and Michael Brenowitz and Almo, {Steven C.} and Xiaoqin Zou and Steven, {Alasdair C.} and David Cowburn and Mark Girvin and Kalpana, {Ganjam V.}",

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doi = "10.1038/s41467-021-22733-9",

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T1 - INI1/SMARCB1 Rpt1 domain mimics TAR RNA in binding to integrase to facilitate HIV-1 replication

AU - Dixit, Updesh

AU - Bhutoria, Savita

AU - Wu, Xuhong

AU - Qiu, Liming

AU - Spira, Menachem

AU - Mathew, Sheeba

AU - Harris, Richard

AU - Adams, Lucas J.

AU - Cahill, Sean

AU - Pathak, Rajiv

AU - Rajesh Kumar, P.

AU - Nguyen, Minh

AU - Acharya, Seetharama A.

AU - Brenowitz, Michael

AU - Almo, Steven C.

AU - Zou, Xiaoqin

AU - Steven, Alasdair C.

AU - Cowburn, David

AU - Girvin, Mark

AU - Kalpana, Ganjam V.

PY - 2021/12/1

Y1 - 2021/12/1

N2 - INI1/SMARCB1 binds to HIV-1 integrase (IN) through its Rpt1 domain and exhibits multifaceted role in HIV-1 replication. Determining the NMR structure of INI1-Rpt1 and modeling its interaction with the IN-C-terminal domain (IN-CTD) reveal that INI1-Rpt1/IN-CTD interface residues overlap with those required for IN/RNA interaction. Mutational analyses validate our model and indicate that the same IN residues are involved in both INI1 and RNA binding. INI1-Rpt1 and TAR RNA compete with each other for IN binding with similar IC50 values. INI1-interaction-defective IN mutant viruses are impaired for incorporation of INI1 into virions and for particle morphogenesis. Computational modeling of IN-CTD/TAR complex indicates that the TAR interface phosphates overlap with negatively charged surface residues of INI1-Rpt1 in three-dimensional space, suggesting that INI1-Rpt1 domain structurally mimics TAR. This possible mimicry between INI1-Rpt1 and TAR explains the mechanism by which INI1/SMARCB1 influences HIV-1 late events and suggests additional strategies to inhibit HIV-1 replication.

AB - INI1/SMARCB1 binds to HIV-1 integrase (IN) through its Rpt1 domain and exhibits multifaceted role in HIV-1 replication. Determining the NMR structure of INI1-Rpt1 and modeling its interaction with the IN-C-terminal domain (IN-CTD) reveal that INI1-Rpt1/IN-CTD interface residues overlap with those required for IN/RNA interaction. Mutational analyses validate our model and indicate that the same IN residues are involved in both INI1 and RNA binding. INI1-Rpt1 and TAR RNA compete with each other for IN binding with similar IC50 values. INI1-interaction-defective IN mutant viruses are impaired for incorporation of INI1 into virions and for particle morphogenesis. Computational modeling of IN-CTD/TAR complex indicates that the TAR interface phosphates overlap with negatively charged surface residues of INI1-Rpt1 in three-dimensional space, suggesting that INI1-Rpt1 domain structurally mimics TAR. This possible mimicry between INI1-Rpt1 and TAR explains the mechanism by which INI1/SMARCB1 influences HIV-1 late events and suggests additional strategies to inhibit HIV-1 replication.

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INI1/SMARCB1 Rpt1 domain mimics TAR RNA in binding to integrase to facilitate HIV-1 replication

Abstract

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