User:Jamie Abbott/Sandbox1

From Proteopedia

Jump to: navigation, search

Histone Acetyltransferase GCN5

Histone Acetyltransferase (HAT) GCN5 is a ~94 kD (837 amino acid) protein. It is a nuclear HAT or A-type HAT. GCN5 belongs to the GCN5-related N-acetyltransferase (GNAT) superfamily that includes the HATs, aminoglycoside N-acetyltransferases, mycothiol synthase, protein N-myristoyltransferase, and the Fem family of amino acyl transferases.[1] Most if not all HATs function in vivo as members of often large multisubunit complexes, many of which were initially characterized as transcriptional regulators. GCN5 has been shown to be part of the STAGA (SPT3-TAFII31-GCN5-L acetylase)[2] complex as well as the TFTC (TATA-binding protein-free TAFII containing)[3] complex.

GCN5 catalyzes the acetylation of specific Lysine residues of histones H3 and H4. More specifically GCN5 is know to acetylate the lysine residues at position 8 and 16 of H4 and 14 of H3 in vivtro. [4]. Acetylation results in the neutralization of charged lysine residues which is hypothesized to weaken histone:DNA contacts[5] as well as alter histone:histone interactions[6]. Chromatin modification more specifically reversible histone acetylation has been associated with gene activation and consequently transcriptional activity for many years.

Sequence alignment of human and yeast GCN5 HAT domain. Motif A-D corresponding to sequence motifs common to GNATs are underlined in green. Amino acid residues involved in hydrogen bonding with AcCoA are marked with ^. The Glutamic acid involved in catalysis is highlighted with *.
Sequence alignment of human and yeast GCN5 HAT domain. Motif A-D corresponding to sequence motifs common to GNATs are underlined in green. Amino acid residues involved in hydrogen bonding with AcCoA are marked with ^. The Glutamic acid involved in catalysis is highlighted with *.

Human GCN5 Histone Acetyltransferase Domain

Drag the structure with the mouse to rotate

== HAT Domain ==Template:STRUCTURE 1z4r The HAT domain of human GCN5 [7] consists of amino acid residues 496-658 with mixed α/β topology. This mixed α/β structure consists of 6 and 7 anti-parallel . The mixed α/β structure of the HAT domain forms an open twisted β sheet surrounded by helices on both sides.


AcCoA is bound via hydrogen bonds in a cleft on the surface of the protein. Residues involved in AcCoA include Val587, Gly589, Gly591, Thr592, Cys579, and Tyr617. There are two long flexible loops in the HAT domain. links helix α1 and strand β1. connects helix α7 and strand β7 and has been associated with substrate binding and specificity. [8] [9]

Weak Stabilizing Interactions I

Cation-Pi Interactions are weak stabilizing interactions that contribute to the integrity of protein structures. A Cation Pi interaction involves the coordination of a cation at the face of an aromatic ring. Often this electrostatic interaction often involves charged Arg and Lys residues coordinated to aromatic side chain of Phe and Trp residues. The aromatic nature and pi orbitals of a Trp or Phe residue create a partial negative charge at the center of the face and assist in coordination of the cation side chain of a Arg or Lys residue. The HAT domain contains a interaction that involves residues Trp519 and Arg515.Cation Pi Interactions

Catalysis

GCN5 catalyzes the transfer of an acetyl group from acetyl coenzyme A () onto the ε-amino group of specific lysine residues present in the amino-terminal tails of each of the core histones, H3 and H4, resulting in the neutralization of a single positive charge. [10] Currently, it has been demonstrated that the catalytic mechanism for yeast GCN5 involves a glutamic acid -173 residue, that acts as a general base. The Glu173 residue must deprotonate the ε-amino group of Lys14 of histone H3 prior to attack on the carbonyl carbon of AcCoA. [11] Comparing the sequence of human GCN5 HAT domain with yeast GCN5 strongly suggests that the catalytic mechanism of acetylation would be very similar. The conserved glutamic acid -173 of yeast GCN5 aligns with glutamic acid -575 of human GCN5 and therefore most likely functions as the general base in acetylation of histones H3 and H4.



Human GCN5 Bromo Domain

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

Jamie Abbott

Retrieved from "http://52.214.119.220/wiki/index.php/User:Jamie_Abbott/Sandbox1"
Personal tools