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 and Ganjam V. Kalpana ()
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Updesh Dixit: Department of Genetics, Albert Einstein College of Medicine
Savita Bhutoria: Department of Genetics, Albert Einstein College of Medicine
Xuhong Wu: Department of Genetics, Albert Einstein College of Medicine
Liming Qiu: University of Missouri
Menachem Spira: Department of Genetics, Albert Einstein College of Medicine
Sheeba Mathew: Department of Genetics, Albert Einstein College of Medicine
Richard Harris: Department of Biochemistry, Albert Einstein College of Medicine
Lucas J. Adams: Laboratory of Structural Biology Research, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health
Sean Cahill: Department of Biochemistry, Albert Einstein College of Medicine
Rajiv Pathak: Department of Genetics, Albert Einstein College of Medicine
P. Rajesh Kumar: Department of Biochemistry, Albert Einstein College of Medicine
Minh Nguyen: Department of Genetics, Albert Einstein College of Medicine
Seetharama A. Acharya: Department of Anatomy & Structural Biology, Albert Einstein College of Medicine
Michael Brenowitz: Department of Biochemistry, Albert Einstein College of Medicine
Steven C. Almo: Department of Biochemistry, Albert Einstein College of Medicine
Xiaoqin Zou: University of Missouri
Alasdair C. Steven: Laboratory of Structural Biology Research, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health
David Cowburn: Department of Biochemistry, Albert Einstein College of Medicine
Mark Girvin: Department of Biochemistry, Albert Einstein College of Medicine
Ganjam V. Kalpana: Department of Genetics, Albert Einstein College of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22733-9

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