Structure of p300 in complex with acyl-CoA variants

Abstract

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.

Metabolic regulation of gene expression through histone acylations

“…Furthermore, p300 can accommodate artificial acyl-CoA analogs, such as 4-pentynoyl-CoA 39 . Kinetic analysis of the Kac, Kpr, Kbu and Kcr activities of p300 confirm that the enzyme catalyzes these acylations, but reveal progressively slower rates commensurate with acyl-chain lengthening 37 . Members of the GNAT and MYST families have a more limited range of non-acetyl acylation activities.…”

“…Beyond its originally described acetyltransferase activity 33,34 , p300 can catalyze histone Kpr 7,35 , Kbu 7 , Kcr 36 , Kbhb 37 as well as Ksucc 38 and Kglu 10 (FIG. 3b).…”

“…Recent structural studies on GCN5 42 and p300 37 bound to a variety of acyl-CoAs revealed molecular mechanisms behind the differing abilities of these HATs to catalyze acylations. Since GCN5 binds to the invariable coenzyme A section of acyl-CoAs (FIG.…”

“…Structural studies of p300 reveal that it contains a deep aliphatic pocket within the active site, a feature absent in GCN5 and other HATs such as TIP60 and MOF 37 . Structure-based mutating of a key Ile residue to Met, which was predicted to open the pocket further, led to enhanced catalysis of Kbu and Kcr.…”

Intricate Effects of α-Amino and Lysine Modifications on Arginine Methylation of the N-Terminal Tail of Histone H4

“…33, 58 Since some HAT enzymes (e.g. p300 and CBP) can accommodate cosubstrates other than acetyl-CoA, 31, 34 the incorporation of diverse acyl-CoAs has been suggested to arise with changes in the acyl-CoA competition for HAT enzymes. 35 This may occur by increasing the concentration of the less prevalent acyl-CoAs by conversion of short-chain fatty acids (SCFAs) and/or reducing the concentration of acetyl-CoA.…”