Investigation of the acetylation mechanism by GCN5 histone acetyltransferase.

The histone acetylation of post-translational modification can be highly dynamic and play a crucial role in regulating cellular proliferation, survival, differentiation and motility. Of the enzymes that mediate post-translation modifications, the GCN5 of the histone acetyltransferase (HAT) proteins...

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Autores principales:	Junfeng Jiang, Junyan Lu, Dan Lu, Zhongjie Liang, Lianchun Li, Sisheng Ouyang, Xiangqian Kong, Hualiang Jiang, Bairong Shen, Cheng Luo
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/fe4bf522592943288c571517a209ae44
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spelling	oai:doaj.org-article:fe4bf522592943288c571517a209ae442021-11-18T07:19:33ZInvestigation of the acetylation mechanism by GCN5 histone acetyltransferase.1932-620310.1371/journal.pone.0036660https://doaj.org/article/fe4bf522592943288c571517a209ae442012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22574209/?tool=EBIhttps://doaj.org/toc/1932-6203The histone acetylation of post-translational modification can be highly dynamic and play a crucial role in regulating cellular proliferation, survival, differentiation and motility. Of the enzymes that mediate post-translation modifications, the GCN5 of the histone acetyltransferase (HAT) proteins family that add acetyl groups to target lysine residues within histones, has been most extensively studied. According to the mechanism studies of GCN5 related proteins, two key processes, deprotonation and acetylation, must be involved. However, as a fundamental issue, the structure of hGCN5/AcCoA/pH3 remains elusive. Although biological experiments have proved that GCN5 mediates the acetylation process through the sequential mechanism pathway, a dynamic view of the catalytic process and the molecular basis for hGCN5/AcCoA/pH3 are still not available and none of theoretical studies has been reported to other related enzymes in HAT family. To explore the molecular basis for the catalytic mechanism, computational approaches including molecular modeling, molecular dynamic (MD) simulation and quantum mechanics/molecular mechanics (QM/MM) simulation were carried out. The initial hGCN5/AcCoA/pH3 complex structure was modeled and a reasonable snapshot was extracted from the trajectory of a 20 ns MD simulation, with considering post-MD analysis and reported experimental results. Those residues playing crucial roles in binding affinity and acetylation reaction were comprehensively investigated. It demonstrated Glu80 acted as the general base for deprotonation of Lys171 from H3. Furthermore, the two-dimensional QM/MM potential energy surface was employed to study the sequential pathway acetylation mechanism. Energy barriers of addition-elimination reaction in acetylation obtained from QM/MM calculation indicated the point of the intermediate ternary complex. Our study may provide insights into the detailed mechanism for acetylation reaction of GCN5, and has important implications for the discovery of regulators against GCN5 enzymes and related HAT family enzymes.Junfeng JiangJunyan LuDan LuZhongjie LiangLianchun LiSisheng OuyangXiangqian KongHualiang JiangBairong ShenCheng LuoPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 5, p e36660 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Junfeng Jiang Junyan Lu Dan Lu Zhongjie Liang Lianchun Li Sisheng Ouyang Xiangqian Kong Hualiang Jiang Bairong Shen Cheng Luo Investigation of the acetylation mechanism by GCN5 histone acetyltransferase.
description	The histone acetylation of post-translational modification can be highly dynamic and play a crucial role in regulating cellular proliferation, survival, differentiation and motility. Of the enzymes that mediate post-translation modifications, the GCN5 of the histone acetyltransferase (HAT) proteins family that add acetyl groups to target lysine residues within histones, has been most extensively studied. According to the mechanism studies of GCN5 related proteins, two key processes, deprotonation and acetylation, must be involved. However, as a fundamental issue, the structure of hGCN5/AcCoA/pH3 remains elusive. Although biological experiments have proved that GCN5 mediates the acetylation process through the sequential mechanism pathway, a dynamic view of the catalytic process and the molecular basis for hGCN5/AcCoA/pH3 are still not available and none of theoretical studies has been reported to other related enzymes in HAT family. To explore the molecular basis for the catalytic mechanism, computational approaches including molecular modeling, molecular dynamic (MD) simulation and quantum mechanics/molecular mechanics (QM/MM) simulation were carried out. The initial hGCN5/AcCoA/pH3 complex structure was modeled and a reasonable snapshot was extracted from the trajectory of a 20 ns MD simulation, with considering post-MD analysis and reported experimental results. Those residues playing crucial roles in binding affinity and acetylation reaction were comprehensively investigated. It demonstrated Glu80 acted as the general base for deprotonation of Lys171 from H3. Furthermore, the two-dimensional QM/MM potential energy surface was employed to study the sequential pathway acetylation mechanism. Energy barriers of addition-elimination reaction in acetylation obtained from QM/MM calculation indicated the point of the intermediate ternary complex. Our study may provide insights into the detailed mechanism for acetylation reaction of GCN5, and has important implications for the discovery of regulators against GCN5 enzymes and related HAT family enzymes.
format	article
author	Junfeng Jiang Junyan Lu Dan Lu Zhongjie Liang Lianchun Li Sisheng Ouyang Xiangqian Kong Hualiang Jiang Bairong Shen Cheng Luo
author_facet	Junfeng Jiang Junyan Lu Dan Lu Zhongjie Liang Lianchun Li Sisheng Ouyang Xiangqian Kong Hualiang Jiang Bairong Shen Cheng Luo
author_sort	Junfeng Jiang
title	Investigation of the acetylation mechanism by GCN5 histone acetyltransferase.
title_short	Investigation of the acetylation mechanism by GCN5 histone acetyltransferase.
title_full	Investigation of the acetylation mechanism by GCN5 histone acetyltransferase.
title_fullStr	Investigation of the acetylation mechanism by GCN5 histone acetyltransferase.
title_full_unstemmed	Investigation of the acetylation mechanism by GCN5 histone acetyltransferase.
title_sort	investigation of the acetylation mechanism by gcn5 histone acetyltransferase.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/fe4bf522592943288c571517a209ae44
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_version_	1718423640282759168

Investigation of the acetylation mechanism by GCN5 histone acetyltransferase.

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