Molecular basis for the recognition of phosphorylated and phosphoacetylated histone h3 by 14-3-3.
Phosphorylation of histone H3 is implicated in transcriptional activation and chromosome condensation, but its immediate molecular function has remained obscure. By affinity chromatography of nuclear extracts against modified H3 tail peptides, we identified 14-3-3 isoforms as proteins that bind these tails in a strictly phosphorylation-dependent manner. Acetylation of lysines 9 and 14 does not impede 14-3-3 binding to serine 10-phosphorylated H3 tails. In vivo, 14-3-3 is inducibly recruited to c-fos and c-jun nucleosomes upon gene activation, concomitant with H3 phosphoacetylation. We have determined the structures of 14-3-3zeta complexed with serine 10-phosphorylated or phosphoacetylated H3 peptides. These reveal a distinct mode of 14-3-3/phosphopeptide binding and provide a structural understanding for the lack of effect of acetylation at lysines 9 and 14 on this interaction. 14-3-3 isoforms thus represent a class of proteins that mediate the effect of histone phosphorylation at inducible genes.
Macdonald
Neil
N
Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, SK10 4TJ, United Kingdom.
Welburn
Julie P I
JP
Noble
Martin E M
ME
Nguyen
Anhco
A
Yaffe
Michael B
MB
Clynes
David
D
Moggs
Jonathan G
JG
Orphanides
George
G
Thomson
Stuart
S
Edmunds
John W
JW
Clayton
Alison L
AL
Endicott
Jane A
JA
Mahadevan
Louis C
LC
D048948:14-3-3 Proteins / Q000737:chemistry / Q000378:metabolism*; D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D006367:HeLa Cells; D006657:Histones / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009707:Nucleosomes / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D012694:Serine / Q000737:chemistry / Q000378:metabolism
D048948:14-3-3 Proteins; D006657:Histones; D009707:Nucleosomes; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012694:Serine