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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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. , 2021. "INI1/SMARCB1 Rpt1 domain mimics TAR RNA in binding to integrase to facilitate HIV-1 replication," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22733-9
    DOI: 10.1038/s41467-021-22733-9
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