Structure of p300 in complex with acyl-CoA variants.
Histone acetylation plays an important role in transcriptional activation. Histones are also modified by chemically diverse acylations that are frequently deposited by p300, a transcriptional coactivator that uses a number of different acyl-CoA cofactors. Here we report that while p300 is a robust acetylase, its activity gets weaker with increasing acyl-CoA chain length. Crystal structures of p300 in complex with propionyl-, crotonyl-, or butyryl-CoA show that the aliphatic portions of these cofactors are bound in the lysine substrate-binding tunnel in a conformation that is incompatible with substrate transfer. Lysine substrate binding is predicted to remodel the acyl-CoA ligands into a conformation compatible with acyl-chain transfer. This remodeling requires that the aliphatic portion of acyl-CoA be accommodated in a hydrophobic pocket in the enzymes active site. The size of the pocket and its aliphatic nature exclude long-chain and charged acyl-CoA variants, presumably explaining the cofactor preference for p300.
European Molecular Biology Laboratory, Grenoble, France.
Zuzanna
Z
Kaczmarska
European Molecular Biology Laboratory, Grenoble, France.
Esther
E
Ortega
Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France.
Afsaneh
A
Goudarzi
Ben May Department of Cancer Research, The University of Chicago, Chicago, Illinois, USA.
He
H
Huang
Ben May Department of Cancer Research, The University of Chicago, Chicago, Illinois, USA.
Sunjoo
http://orcid.org/0000-0003-1283-9244
S
Kim
European Molecular Biology Laboratory, Grenoble, France.
José A
JA
Márquez
Ben May Department of Cancer Research, The University of Chicago, Chicago, Illinois, USA.
Yingming
Y
Zhao
Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, France.
Saadi
S
Khochbin
European Molecular Biology Laboratory, Grenoble, France.
Daniel
http://orcid.org/0000-0001-9158-5507
D
Panne
D003065:Coenzyme A / Q000737:chemistry* / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation
D008024:Ligands; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D003065:Coenzyme A