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. 2024 Jan;254(Pt 2):127717.
doi: 10.1016/j.ijbiomac.2023.127717. Epub 2023 Nov 2.

Structural basis for the role of C-terminus acidic tail of Saccharomyces cerevisiae ubiquitin-conjugating enzyme (Rad6) in E3 ligase (Bre1) mediated recognition of histones

Pawan Yadav  1 , Manish Gupta  2 , Rushna Wazahat  1 , Zeyaul Islam  3 , Susan E Tsutakawa  4 , Mohan Kamthan  1 , Pankaj Kumar  5
Affiliations

Structural basis for the role of C-terminus acidic tail of Saccharomyces cerevisiae ubiquitin-conjugating enzyme (Rad6) in E3 ligase (Bre1) mediated recognition of histones

Pawan Yadav et al. Int J Biol Macromol. 2024 Jan.

Abstract

Ubiquitination of histone H2B on chromatin is key to gene regulation. E3 ligase Bre1 and E2 Rad6 in Saccharomyces cerevisiae associate together to catalyze mono-ubiquitination at histone H2BK123. Prior studies identified the role of a highly dynamic C-terminal acidic tail of Rad6 indispensable for H2BK123 mono-ubiquitination. However, the mechanistic basis for the Rad6-acidic tail role remained elusive. Using different structural and biophysical approaches, this study for the first time uncovers the direct role of Rad6-acidic tail in interaction with the Bre1 Rad6-Binding Domain (RBD) and recognition of histones surface to facilitate histone H2B mono-ubiquitination. A combination of NMR, SAXS, ITC, site-directed mutagenesis and molecular dynamics studies reveal that RBD domain of Bre1 interacts with Rad6 to stabilize the dynamics of acidic tail. This Bre1-RBD mediated stability in acidic tail of Rad6 could be one of the key factors for facilitating correct recognition of histone surface and ubiquitin-transfer at H2BK123. We provide biophysical evidence that Rad6-acidic tail and a positivity charged surface on histone H2B are involved in recognition of E2:Histones. Taken together, this study uncovers the mechanistic basis for the role of Rad6-acidic in Bre1-RBD mediated recognition of histone surface that ensure the histone H2B mono-ubiquitination.

Keywords: Acidic tail; Bre1; Histones; Mono-ubiquitination; Rad6.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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