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From Proteopedia
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.
β-beta sheets</scene> == 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 ICation-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 CatalysisGCN5 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.
Bromo DomainThe bromodomain is a highly conserved domain found to be a part of many chromatin remodeling proteins and nearly all HAT structures contain a bromodomain. This 110 amino acid motif was originally identified as a sequence motif common to the Drosophila brahma and female-sterile homeotic proteins, the yeast SWI2/SNF2 proteins and the human CCG1 protein [12][13] While the bromo domain is fairly close to the HAT domain of GCN5 no evidence suggests that it is involved in or necessary for histone acetyl transferase activity. The GCN5 bromodomain is 71% α-helical domain of 110 amino acids with no β structures. The bromodoamin forms a consisting of helices αZ,αA,αB,and αC. In this four helix bundle the anti-parallel adjacent α helices pack together with angles approximately 18° to 20° to the helical axes. This arrangment of helices commonly found in helix bundles forms the "Ridges and Grooves" model. The model allow for the fitting of residues from one helix into the grooves of another. Additionally, the up-and-down four-helix bundle of the GCN5 bromodomain has left handed topology as a result of the orientation of the long ZA loop.  Weak Stabilizing Interactions IISalt Bridge Formation is another example of weak interactions that can stabilize the secondary structures of proteins. The formation of salt bridges can increase packing density, increase hydrophobic core packing, and even decrease the length of surface loops.[14] [15]The formation of salt bridges involves both hydrogen bonding and electrostatic interactions. Salt bridges frequently occur between the anionic carboxylate of either Asp of Glu and cationic ammonium of Lys or Arg. Other residues with ionizable side chains, such as His, Tyr, and Ser may also participate in the formation of salt bridges. There are two ways in which to characterize salt bridge charge-charge interactions; where the cation and anion are hydrogen bonded to each other or the cation and anion are not hydrogen bonded to each other. The distance of salt bridges typically do not exceed 3.5 Å. The bromodomain has five involving residues 805, 822, 767, 770, 813, 816,828,831,780, and 776. One of these bridges involves the stabilization of helices αB and αC while another forms in the AZ Loop and may contribute the stabilization of the 3z helix.
Protein-Protein InteractionsHelices αZ and αA are connected by the ZA loop while helices αB and αC are connected by the BC loop. A two additional helices exist in the long ZA loop termed 3z and αA'. The ZA and BC loops pack together to form a hydrophobic pocket that may be involved in protein-protein interactions. [16] The is lined with residues Val757, Ala762, Tyr765, Tyr807, and Tyr814. The surface of this pocket is essentially the surface of the hydrophobic core of the bromodomain and some of the same residues that line this hydrophobic pocket are involved in the formation of the hydrophobic core. Residues that line the interior of the hydrophobic cavity include F753, V757, Y765, I773, D774, V800, N803, C804, Y807, N808, and Y814.
   
The bromodomain is separated from the HAT domain by 57 amino acids residues which contain an ADA2 interaction domain.[17]
Post-Translational ModificationsGCN5 contains one known site for posttranslational modification. A Try residue at position 734 is subject to phosphorylation by Tyrosine kinases. [18] [19] Residue Tyr734 is located in the helix of the bromodomain. The may act as a molecular switch that serves to activate or deactivate GCN5 and more specifically affect the bromodomain.
PCAF_N DomainStructural PredictionThere is no known structure for the PCAF_N domain or p300/CBP assocaited factor N-terminal domain. From the known sequence for the PCAF_N domain, structural predictions can be generated for this domain. Predictprotein generates___________.The PCAF_N domain was predicted to be a mixed α+β structure. The secondary structural predictions indicated that the domain would consist of 31% helical, 4% beta strands, and 65% loop. Other important structural features that were predicted included one disulfide bond and three sites for postranslational modifications. Posttranslational modification sites included a N-glycosylation site, a Casein kinase II phosphorylation site, and a N-myristoylation site. Taking advantage of Protein Homology/analogY Recognition Engine or PHYRE models for the PCAF_N domain can be generated. http://www.sbg.bio.ic.ac.uk/phyre/html/index.html https://www.predictprotein.org/
Evoultionary ConservationStructural Homology 
References
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