Protein Acetylation Signaling Pathway
Lysine acetylation is a reversible post-translational modification that plays a crucial role in regulating protein function, chromatin structure, and gene expression. Many transcriptional coactivators possess intrinsic acetylase activity, while transcriptional corepressors are associated with deacetylase activity. Acetylation complexes (such as CBP/ p300 and PCAF) or deacetylation complexes (such as Sin3, NuRD, NcoR, and SMRT) are recruited to DNA-bound transcription factors (TFs) in response to signaling pathways. Histone hyperacetylation by histone acetyltransferases (HATs) is associated with transcriptional activation, whereas histone deacetylation by histone deacetylases (HDACs) is associated with transcriptional repression. Histone acetylation stimulates transcription by remodeling higher order chromatin structure, weakening histone-DNA interactions, and providing binding sites for transcriptional activation complexes containing proteins that possess bromodomains, which bind acetylated lysine. Histone deacetylation represses transcription through an inverse mechanism involving the assembly of compact higher order chromatin and the exclusion of bromodomain-containing transcription activation complexes. Histone hypoacetylation is a hallmark of silent heterochromatin. Site-specific acetylation of a growing number of non-histone proteins has been shown to regulate their activity, localization, specific interactions, and stability/degradation. Remarkably, recent advances in mass spectrometry technologies allowed high resolution mapping of most of the acetylation sites in all the proteome. These studies demonstrated that the “acetylome” encompasses nearly ~3600 acetylation sites in roughly ~1750 proteins, suggesting that this modification is one of the most abundant chemical modifications in nature. Indeed, it appears that this mark can influence the activity of proteins in diverse biological processes, including chromatin remodeling, cell cycle, splicing, nuclear transport, mitochondrial biology, and actin nucleation. At an organismal level, acetylation plays an important role in immunity, circadian rhythmicity, and memory formation. Protein acetylation is becoming a favorable target in drug design for numerous disease conditions.
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We would like to thank Prof. Raul Mostoslavsky, Harvard Medical School, Boston, MA, for contributing to this diagram.
created November 2002
revised September 2012