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

doi:10.1016/j.str.2021.01.010

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

Structure. 2021 Aug 5;29(8):886-898.e6. doi: 10.1016/j.str.2021.01.010. Epub 2021 Feb 15.

Authors

Sriram Aiyer¹, G V T Swapna¹, Li-Chung Ma¹, Gaohua Liu², Jingzhou Hao³, Gordon Chalmers⁴, Brian C Jacobs⁵, Gaetano T Montelione⁶, Monica J Roth⁷

Affiliations

¹ Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854, USA; Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854, USA.
² Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854, USA.
³ Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854, USA; Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Sciences, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
⁴ Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Sciences, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
⁵ Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854, USA.
⁶ Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854, USA; Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Sciences, Rensselaer Polytechnic Institute, Troy, NY 12180, USA. Electronic address: monteg3@rpi.edu.
⁷ Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854, USA; Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854, USA. Electronic address: roth@rwjms.rutgers.edu.

Abstract

The extraterminal (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 the BRD3 ET domain and either the 79-residue murine leukemia virus integrase (IN) C-terminal domain (IN_329-408) or its 22-residue IN tail peptide (IN_386-407) alone reveal similar intermolecular three-stranded β-sheet formations. ¹⁵N relaxation studies reveal a 10-residue linker region (IN_379-388) tethering the SH3 domain (IN_329-378) to the ET-binding motif (IN_389-405):ET complex. This linker has restricted flexibility, affecting its potential range of orientations in the IN:nucleosome complex. The complex of the ET-binding peptide of the host NSD3 protein (NSD3_148-184) and the BRD3 ET domain includes a similar three-stranded β-sheet interaction, but the orientation of the β hairpin is flipped compared with 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.

Keywords: BET proteins; BRD3; Moloney murine leukemia virus; NSD3; extraterminal domain; integrase; interdomain dynamics; isotope peptide labeling; solution NMR.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Binding Sites
Histone-Lysine N-Methyltransferase / chemistry*
Histone-Lysine N-Methyltransferase / metabolism
Humans
Hydrophobic and Hydrophilic Interactions
Integrases / chemistry*
Integrases / metabolism
Leukemia Virus, Murine / enzymology*
Models, Molecular
Nuclear Proteins / chemistry*
Nuclear Proteins / metabolism
Protein Binding
Protein Conformation
Transcription Factors / chemistry*
Viral Proteins / chemistry
Viral Proteins / metabolism

Substances

BRD3 protein, human
Nuclear Proteins
Transcription Factors
Viral Proteins
Histone-Lysine N-Methyltransferase
NSD3 protein, human
Integrases

Abstract

Publication types

MeSH terms

Substances

Grants and funding