Chemical Synthesis of Phosphorylated Histone H2A at Tyr57 Reveals Insight into the Inhibition Mode of the SAGA Deubiquitinating Module

Muhammad Jbara, Suman Kumar Maity, Michael Morgan, Cynthia Wolberger, Ashraf Brik

Research output: Contribution to journalArticle

Abstract

Monoubiquitination of histone H2B plays a central role in transcription activation and is required for downstream histone-methylation events. Deubiquitination of H2B by the Spt-Ada-Gcn5 acetyltransferase (SAGA) coactivator complex is regulated by a recently discovered histone mark, phosphorylated H2AY57 (H2AY57p), which inhibits deubiquitination of H2B by the SAGA complex as well as restricting demethylation of H3 and increasing its acetylation. Evidence for the effect of H2AY57p, however, was indirect and was investigated in vivo by monitoring the effects of chemical inhibition of Tyr kinase CK2 or by mutating the phosphorylation site. We applied the total chemical synthesis of proteins to prepare H2AY57p efficiently and study the molecular details of this regulation. This analogue, together with semisynthetically prepared ubiquitinated H2B, enabled us to provide direct evidence for the cross-talk between those two marks and the inhibition of SAGA activity by H2AY57p.

Original languageEnglish (US)
JournalAngewandte Chemie - International Edition
DOIs
StateAccepted/In press - 2016

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Acetylation
Phosphorylation
Acetyltransferases
Methylation
Transcription
Histones
Chemical activation
Proteins
Monitoring
Phosphotransferases

Keywords

  • Chemical protein synthesis
  • Deubiquitination
  • Phosphorylation
  • Proteins
  • Total synthesis

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis

Cite this

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title = "Chemical Synthesis of Phosphorylated Histone H2A at Tyr57 Reveals Insight into the Inhibition Mode of the SAGA Deubiquitinating Module",
abstract = "Monoubiquitination of histone H2B plays a central role in transcription activation and is required for downstream histone-methylation events. Deubiquitination of H2B by the Spt-Ada-Gcn5 acetyltransferase (SAGA) coactivator complex is regulated by a recently discovered histone mark, phosphorylated H2AY57 (H2AY57p), which inhibits deubiquitination of H2B by the SAGA complex as well as restricting demethylation of H3 and increasing its acetylation. Evidence for the effect of H2AY57p, however, was indirect and was investigated in vivo by monitoring the effects of chemical inhibition of Tyr kinase CK2 or by mutating the phosphorylation site. We applied the total chemical synthesis of proteins to prepare H2AY57p efficiently and study the molecular details of this regulation. This analogue, together with semisynthetically prepared ubiquitinated H2B, enabled us to provide direct evidence for the cross-talk between those two marks and the inhibition of SAGA activity by H2AY57p.",
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AU - Jbara, Muhammad

AU - Maity, Suman Kumar

AU - Morgan, Michael

AU - Wolberger, Cynthia

AU - Brik, Ashraf

PY - 2016

Y1 - 2016

N2 - Monoubiquitination of histone H2B plays a central role in transcription activation and is required for downstream histone-methylation events. Deubiquitination of H2B by the Spt-Ada-Gcn5 acetyltransferase (SAGA) coactivator complex is regulated by a recently discovered histone mark, phosphorylated H2AY57 (H2AY57p), which inhibits deubiquitination of H2B by the SAGA complex as well as restricting demethylation of H3 and increasing its acetylation. Evidence for the effect of H2AY57p, however, was indirect and was investigated in vivo by monitoring the effects of chemical inhibition of Tyr kinase CK2 or by mutating the phosphorylation site. We applied the total chemical synthesis of proteins to prepare H2AY57p efficiently and study the molecular details of this regulation. This analogue, together with semisynthetically prepared ubiquitinated H2B, enabled us to provide direct evidence for the cross-talk between those two marks and the inhibition of SAGA activity by H2AY57p.

AB - Monoubiquitination of histone H2B plays a central role in transcription activation and is required for downstream histone-methylation events. Deubiquitination of H2B by the Spt-Ada-Gcn5 acetyltransferase (SAGA) coactivator complex is regulated by a recently discovered histone mark, phosphorylated H2AY57 (H2AY57p), which inhibits deubiquitination of H2B by the SAGA complex as well as restricting demethylation of H3 and increasing its acetylation. Evidence for the effect of H2AY57p, however, was indirect and was investigated in vivo by monitoring the effects of chemical inhibition of Tyr kinase CK2 or by mutating the phosphorylation site. We applied the total chemical synthesis of proteins to prepare H2AY57p efficiently and study the molecular details of this regulation. This analogue, together with semisynthetically prepared ubiquitinated H2B, enabled us to provide direct evidence for the cross-talk between those two marks and the inhibition of SAGA activity by H2AY57p.

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