Structure of the Taz2 domain of p300: insights into ligand binding

Abstract

CBP and its paralog p300 are histone acetyl transferases that regulate gene expression by interacting with multiple transcription factors via specialized domains. The structure of a segment of human p300 protein (residues 1723-1836) corresponding to the extended zinc-binding Taz2 domain has been investigated. The crystal structure was solved by the SAD approach utilizing the anomalous diffraction signal of the bound Zn ions. The structure comprises an atypical helical bundle stabilized by three Zn ions and closely resembles the solution structures determined previously for shorter peptides. Residues 1813-1834 from the current construct form a helical extension of the C-terminal helix and make extensive crystalcontact interactions with the peptide-binding site of Taz2, providing additional insights into the mechanism of the recognition of diverse transactivation domains (TADs) by Taz2. On the basis of these results and molecular modeling, a hypothetical model of the binding of phosphorylated p53 TAD1 to Taz2 has been proposed.

Structure of p300 bound to MEF2 on DNA reveals a mechanism of enhanceosome assembly

“…This unusually long helix makes no contacts with the rest of the TAZ domain but engages in extensive interactions with symmetry related molecules in crystal (70). It was not observed in the NMR structure of the same domain bound to p53 because a shorter p300 fragment (1723–1812) was used (14).…”

Role of Intrinsic Protein Disorder in the Function and Interactions of the Transcriptional Coactivators CREB-binding Protein (CBP) and p300

“…The promiscuity of this binding site has resulted in some potentially misleading interactions in x-ray structures. In the crystal structure of free TAZ2, a C-terminal extension of the ␣ 4 helix extends beyond the globular core and docks to the hydrophobic surface on a neighboring molecule in the crystal lattice, mimicking the interactions of TAZ2 with the amphipathic helices of regulatory IDRs (33). The long ␣ 4 helix observed in the x-ray structure appears to be stabilized by lattice contacts.…”

Phosphorylation of glucocorticoid receptor tau1c transactivation domain enhances binding to CREB binding protein (CBP) TAZ2

“…Structural studies have revealed that TAZ2 forms a four a-helix core structure linked by three short loops that comprise zinc binding motifs [14,22] and those of TAZ2 in complex with p53, Stat1 and E1a reveal that a-helical TAD segments dock against different surfaces of the TAZ2 a-helical core with different binding modes [14][15][16][17]. Since our studies raise the possibility that GR helical segments could be responsible for binding to the TAZ2 (Fig.…”