title: Structural Insights into Histone Crotonyl-Lysine Recognition by the AF9 YEATS Domain.
abstract: Histone lysine acylations play an important role in the regulation of gene transcription in chromatin. Unlike histone acetyl-lysine, molecular recognition of a recently identified crotonyl-lysine mark is much less understood. Here, we report that the YEATS domain of AF9 preferentially binds crotonyl-lysine over acetyl-lysine in histone H3. Nuclear magnetic resonance structural analysis reveals that crotonyl-lysine of histone H3 lysine 18 is engulfed deep in an aromatic cage of the YEATS domain where the carbonyl oxygen of crotonyl-lysine forms a hydrogen bond with the backbone amide of protein residue Tyr78. The crotonyl-lysine, through its unique electron-rich double-bond side chain, engages π-π aromatic stacking and extended hydrophobic/aromatic interactions with the YEATS domain compared with acetyl-lysine. Our mutational analysis confirmed key protein residues Phe59 and Tyr78 for crotonyl-lysine recognition. Importantly, our findings present a new structural mechanism of protein-protein interactions mediated by histone lysine crotonylation, and show how the cells interpret acyl-lysine marks in different biological contexts.
authors.affiliation: The First Hospital and Institute of Epigenetic Medicine, Jilin University, Changchun 130061, China; Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: qiang.zhang@mssm.edu.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: The First Hospital and Institute of Epigenetic Medicine, Jilin University, Changchun 130061, China; Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Zeng
authors.affiliation: The First Hospital and Institute of Epigenetic Medicine, Jilin University, Changchun 130061, China.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Zhao
authors.affiliation: The First Hospital and Institute of Epigenetic Medicine, Jilin University, Changchun 130061, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ju
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Konuma
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: ming-ming.zhou@mssm.edu.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Zhou
mesh_terms: D020816:Amino Acid Motifs; D001665:Binding Sites; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006657:Histones / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008239:Lysine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010649:Phenylalanine / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism
chemical_list: D006657:Histones; C489901:MLLT3 protein, human; D009687:Nuclear Proteins; D011994:Recombinant Proteins; C576157:epsilon-N-crotonyllysine; C002315:N(alpha)-acetyllysine; D014443:Tyrosine; D010649:Phenylalanine; D008239:Lysine