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A common binding motif in the ET domain of BRD3 forms polymorphic structural interfaces with host and viral proteins

View ORCID ProfileSriram Aiyer, View ORCID ProfileG.V.T. Swapna, Li-Chung Ma, View ORCID ProfileGaohua Liu, View ORCID ProfileJingzhou Hao, View ORCID ProfileGordon Chalmers, View ORCID ProfileBrian C. Jacobs, View ORCID ProfileGaetano T. Montelione, View ORCID ProfileMonica J. Roth
doi: https://doi.org/10.1101/2020.09.21.306696
Sriram Aiyer
1Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 675 Hoes Lane, Piscataway, NJ, 08854 USA
2Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 675 Hoes Lane, Piscataway, NJ, 08854 USA
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G.V.T. Swapna
1Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 675 Hoes Lane, Piscataway, NJ, 08854 USA
2Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 675 Hoes Lane, Piscataway, NJ, 08854 USA
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Li-Chung Ma
1Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 675 Hoes Lane, Piscataway, NJ, 08854 USA
2Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 675 Hoes Lane, Piscataway, NJ, 08854 USA
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Gaohua Liu
2Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 675 Hoes Lane, Piscataway, NJ, 08854 USA
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Jingzhou Hao
2Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 675 Hoes Lane, Piscataway, NJ, 08854 USA
3Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Sciences, Rensselaer Polytechnic Institute, Troy, NY, 12180 USA
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Gordon Chalmers
3Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Sciences, Rensselaer Polytechnic Institute, Troy, NY, 12180 USA
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Brian C. Jacobs
1Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 675 Hoes Lane, Piscataway, NJ, 08854 USA
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Gaetano T. Montelione
2Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 675 Hoes Lane, Piscataway, NJ, 08854 USA
3Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Sciences, Rensselaer Polytechnic Institute, Troy, NY, 12180 USA
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  • For correspondence: roth@rwjms.rutgers.edu monteg3@rpi.edu
Monica J. Roth
1Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 675 Hoes Lane, Piscataway, NJ, 08854 USA
2Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 675 Hoes Lane, Piscataway, NJ, 08854 USA
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  • For correspondence: roth@rwjms.rutgers.edu monteg3@rpi.edu
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Summary

The extra-terminal (ET) domain of BRD3 is conserved among BET proteins (BRD2, BRD3, BRD4), interacting with multiple host and viral protein-protein networks. Solution NMR structures of complexes formed between BRD3-ET domain with either the 79-residue murine leukemia virus integrase (IN) C-terminal domain (IN329-408), or its 22-residue IN tail peptide (TP) (IN386-407) alone, reveal similar intermolecular three-stranded β-sheet formation. 15N relaxation studies reveal a 10-residue linker region (IN379-388) tethering the SH3 domain (IN329-378) to the ET-binding motif (IN389-405)-ET complex. This linker has restricted flexibility, impacting its potential range of orientations in the IN - nucleosome complex. The complex of the ET-binding peptide of host NSD3 protein (NSD3148-184) and BRD3-ET domain includes a similar three-stranded β-sheet interaction, but the orientation of the β−hairpin is flipped compared to the two IN : ET complexes. These studies expand our understanding of molecular recognition polymorphism in complexes of ET-binding motifs with viral and host proteins.

Highlights

  • The BRD3 ET domain binds to key peptide motifs of diverse host and viral proteins.

  • These complexes reveal conformational plasticity in molecular recognition.

  • NMR studies demonstrate restricted interdomain motion in the IN CTD / ET complex.

  • A cost-effective approach is described for producing isotopically-labeled peptides.

Etoc Blurb We address structurally how the MLV Integrase (IN) usurps the host function of the BET protein through comparative studies of the IN : Brd3 ET complex with that of the host NSD3. MLV integration and thus its pathogenesis is driven through protein interactions of the IN : BET family.

Competing Interest Statement

GL is an officer of Nexomics Biosciences, Inc. GTM is a founder of Nexomics Biosciences, Inc. These relationships do not present competing interests with respect to this paper.

Footnotes

  • COI Statement. GL is an officer of Nexomics Biosciences, Inc. GTM is a founder of Nexomics Biosciences, Inc.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted September 21, 2020.
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A common binding motif in the ET domain of BRD3 forms polymorphic structural interfaces with host and viral proteins
Sriram Aiyer, G.V.T. Swapna, Li-Chung Ma, Gaohua Liu, Jingzhou Hao, Gordon Chalmers, Brian C. Jacobs, Gaetano T. Montelione, Monica J. Roth
bioRxiv 2020.09.21.306696; doi: https://doi.org/10.1101/2020.09.21.306696
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A common binding motif in the ET domain of BRD3 forms polymorphic structural interfaces with host and viral proteins
Sriram Aiyer, G.V.T. Swapna, Li-Chung Ma, Gaohua Liu, Jingzhou Hao, Gordon Chalmers, Brian C. Jacobs, Gaetano T. Montelione, Monica J. Roth
bioRxiv 2020.09.21.306696; doi: https://doi.org/10.1101/2020.09.21.306696

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