User:Jamie Abbott/Sandbox1
From Proteopedia
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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. Histone acetylation is an important
HAT Domain
The HAT domain of human GCN5 [4] consists of amino acid residues 496-658 with mixed α/β topology. This mixed α/β structure consists of 7 and seven anti-parallel . AcCoA is binds via hydrogen bonds in a cleft on the surface of the protein. Residues involved in hydrogen bonding AcCoA include Val587, Gly589, Gly591, Thr592, Cys579, and Tyr617.
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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. [5] 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. [6] 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 aligns with glutamic acid -575 of human GCN5 and therefore Glu575 may function as the general base in acetylation of histones H3 and H4.
Bromo Domain
The bromodomain is a highly conserved domain found to be a part of many chromatin remodeling proteins. Nearly all HAT structures contain a bromodomain. The bromodoamin of human GCN5 is 110 amino acids and forms a (αZ,αA,αB,and αC). Helices αZ and αA are connected by the ZA loop while helices αB and αC are connected by the BC loop. 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. Loops ZA and BC pack together to form a hydrophobic pocket that may be involved in protein-protein interactions.[7]
The bromodomain is separated from the HAT domain by 57 amino acids residues which contain an ADA2 interaction domain.[8]
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Evoultionary Conservation
References
- ↑ Vetting MW, S de Carvalho LP, Yu M, Hegde SS, Magnet S, Roderick SL, Blanchard JS. Structure and functions of the GNAT superfamily of acetyltransferases. Arch Biochem Biophys. 2005 Jan 1;433(1):212-26. PMID:15581578 doi:10.1016/j.abb.2004.09.003
- ↑ Martinez E, Kundu TK, Fu J, Roeder RG. A human SPT3-TAFII31-GCN5-L acetylase complex distinct from transcription factor IID. J Biol Chem. 1998 Sep 11;273(37):23781-5. PMID:9726987
- ↑ Brand M, Yamamoto K, Staub A, Tora L. Identification of TATA-binding protein-free TAFII-containing complex subunits suggests a role in nucleosome acetylation and signal transduction. J Biol Chem. 1999 Jun 25;274(26):18285-9. PMID:10373431
- ↑ Schuetz A, Bernstein G, Dong A, Antoshenko T, Wu H, Loppnau P, Bochkarev A, Plotnikov AN. Crystal structure of a binary complex between human GCN5 histone acetyltransferase domain and acetyl coenzyme A. Proteins. 2007 Jul 1;68(1):403-7. PMID:17410582 doi:10.1002/prot.21407
- ↑ Schuetz A, Bernstein G, Dong A, Antoshenko T, Wu H, Loppnau P, Bochkarev A, Plotnikov AN. Crystal structure of a binary complex between human GCN5 histone acetyltransferase domain and acetyl coenzyme A. Proteins. 2007 Jul 1;68(1):403-7. PMID:17410582 doi:10.1002/prot.21407
- ↑ Tanner KG, Langer MR, Kim Y, Denu JM. Kinetic mechanism of the histone acetyltransferase GCN5 from yeast. J Biol Chem. 2000 Jul 21;275(29):22048-55. PMID:10811654 doi:10.1074/jbc.M002893200
- ↑ Dhalluin C, Carlson JE, Zeng L, He C, Aggarwal AK, Zhou MM. Structure and ligand of a histone acetyltransferase bromodomain. Nature. 1999 Jun 3;399(6735):491-6. PMID:10365964 doi:10.1038/20974
- ↑ Candau R, Zhou JX, Allis CD, Berger SL. Histone acetyltransferase activity and interaction with ADA2 are critical for GCN5 function in vivo. EMBO J. 1997 Feb 3;16(3):555-65. PMID:9034338 doi:10.1093/emboj/16.3.555
