A Subset of Human Bromodomains Recognizes Butyryllysine and Crotonyllysine Histone Peptide Modifications

E Megan Flynn; Oscar W Huang; Florence Poy; Mariano Oppikofer; Steve F Bellon; Yong Tang; Andrea G Cochran

doi:10.1016/j.str.2015.08.004

A Subset of Human Bromodomains Recognizes Butyryllysine and Crotonyllysine Histone Peptide Modifications

Structure. 2015 Oct 6;23(10):1801-1814. doi: 10.1016/j.str.2015.08.004. Epub 2015 Sep 10.

Authors

E Megan Flynn¹, Oscar W Huang¹, Florence Poy², Mariano Oppikofer¹, Steve F Bellon², Yong Tang³, Andrea G Cochran⁴

Affiliations

¹ Department of Early Discovery Biochemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
² Department of Structural Biology, Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, USA.
³ Department of Structural Biology, Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, USA. Electronic address: yongtang@broadinstitute.org.
⁴ Department of Early Discovery Biochemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: cochran.andrea@gene.com.

PMID: 26365797
DOI: 10.1016/j.str.2015.08.004

Abstract

Bromodomains are epigenetic readers that are recruited to acetyllysine residues in histone tails. Recent studies have identified non-acetyl acyllysine modifications, raising the possibility that these might be read by bromodomains. Profiling the nearly complete human bromodomain family revealed that while most human bromodomains bind only the shorter acetyl and propionyl marks, the bromodomains of BRD9, CECR2, and the second bromodomain of TAF1 also recognize the longer butyryl mark. In addition, the TAF1 second bromodomain is capable of binding crotonyl marks. None of the human bromodomains tested binds succinyl marks. We characterized structurally and biochemically the binding to different acyl groups, identifying bromodomain residues and structural attributes that contribute to specificity. These studies demonstrate a surprising degree of plasticity in some human bromodomains but no single factor controlling specificity across the family. The identification of candidate butyryl- and crotonyllysine readers supports the idea that these marks could have specific physiological functions.

MeSH terms

Acylation
Binding Sites
Butyrates / chemistry
Butyrates / metabolism
Crotonates / chemistry
Crotonates / metabolism
Crystallography, X-Ray
Epigenesis, Genetic
Escherichia coli / genetics
Escherichia coli / metabolism
Gene Expression
Histone Acetyltransferases / chemistry*
Histone Acetyltransferases / genetics
Histone Acetyltransferases / metabolism
Histones / chemistry*
Histones / genetics
Histones / metabolism
Humans
Kinetics
Lysine / chemistry*
Lysine / metabolism
Models, Molecular
Protein Array Analysis
Protein Binding
Protein Processing, Post-Translational*
Protein Structure, Secondary
Protein Structure, Tertiary
Recombinant Proteins / chemistry
Recombinant Proteins / genetics
Recombinant Proteins / metabolism
TATA-Binding Protein Associated Factors / chemistry*
TATA-Binding Protein Associated Factors / genetics
TATA-Binding Protein Associated Factors / metabolism
Transcription Factor TFIID / chemistry*
Transcription Factor TFIID / genetics
Transcription Factor TFIID / metabolism
Transcription Factors / chemistry*
Transcription Factors / genetics
Transcription Factors / metabolism
Water / chemistry
Water / metabolism

Substances

BRD9 protein, human
Butyrates
Cecr2 protein, human
Crotonates
Histones
Recombinant Proteins
TATA-Binding Protein Associated Factors
Transcription Factor TFIID
Transcription Factors
Water
Histone Acetyltransferases
TATA-binding protein associated factor 250 kDa
Lysine

Associated data

PDB/4YY4
PDB/4YY6
PDB/4YYD
PDB/4YYG
PDB/4YYH
PDB/4YYI
PDB/4YYJ
PDB/4YYK
PDB/4YYM
PDB/4YYN