Lysine acetylation is a widespread and reversible post-translational modification (PTM) of proteins, where an acetyl group is added to a lysine residue. This modification acts as a molecular switch, altering how proteins function within cells. It is a fundamental biological process, impacting a wide array of cellular activities in both eukaryotic and prokaryotic cells. This dynamic process allows cells to fine-tune protein activity and respond to various cues.
The Enzymes of Lysine Acetylation
The balance of lysine acetylation is maintained by two opposing groups of enzymes: “writers” and “erasers.” Lysine acetyltransferases (KATs), also known as histone acetyltransferases (HATs), are the “writer” enzymes that add acetyl groups to lysine residues. These enzymes transfer an acetyl group from acetyl coenzyme A (acetyl-CoA) to a lysine residue on a target protein.
Conversely, lysine deacetylases (KDACs), also known as histone deacetylases (HDACs), act as “erasers” by removing these acetyl groups. This removal restores the positive charge of the lysine residue, which alters the protein’s properties and interactions. The reversibility of this process, facilitated by the opposing actions of KATs and KDACs, enables dynamic regulation of protein function. KDACs include zinc-dependent deacetylases and NAD+-dependent sirtuins.
How Lysine Acetylation Shapes Gene Expression
One well-understood role of lysine acetylation involves histones, proteins that package DNA into compact structures called chromatin within the cell nucleus. Histones have positively charged tails that interact with negatively charged DNA, helping to condense chromatin. Acetylation of specific lysine residues on these histone tails neutralizes their positive charge.
This neutralization weakens the interaction between histones and DNA, leading to a more relaxed or “open” chromatin structure. An open chromatin structure makes DNA more accessible to the cellular machinery responsible for transcription, the process of copying genetic information from DNA into RNA, thereby promoting gene expression. Conversely, when KDACs remove acetyl groups from histones, chromatin becomes more condensed, making DNA less accessible and repressing gene expression. This mechanism of modifying gene activity without altering the underlying DNA sequence is a fundamental aspect of epigenetics, influencing how genes are turned on or off in different cell types or in response to environmental signals.
Beyond DNA: Regulating Cellular Functions
While histone acetylation is a prominent example, the impact of lysine acetylation extends beyond DNA packaging and gene expression, influencing numerous non-histone proteins throughout the cell. Proteomic analyses reveal that a significant portion of the cell’s proteins are acetylated, affecting a wide array of cellular processes. This modification can alter protein stability, influencing how long a protein remains active.
Lysine acetylation also modulates enzyme activity, acting as a direct switch to turn enzymes on or off, or to fine-tune their efficiency. The modification can impact protein-protein interactions, dictating which proteins can bind to each other and form functional complexes. It can also influence the subcellular localization of proteins, directing them to specific compartments within the cell. For example, acetylation plays a role in metabolic pathways, affecting the activity of enzymes involved in processes like glycolysis or fatty acid oxidation. It is also involved in DNA repair mechanisms and various cell signaling pathways, allowing cells to adapt to changing conditions and maintain cellular homeostasis.
Lysine Acetylation and Human Health
Dysregulation of lysine acetylation has significant implications for human health, contributing to the development and progression of various diseases. Imbalances in the activity of KATs or KDACs, or errors in the acetylation marks, can disrupt normal cellular processes. In cancer, many KATs and KDACs are altered, acting as oncogenes (cancer-promoting) or tumor suppressors (cancer-preventing). This makes enzymes involved in acetylation attractive targets for new therapies, with inhibitors being explored as potential cancer treatments.
Beyond cancer, altered lysine acetylation is linked to metabolic disorders such as diabetes and obesity, reflecting its widespread role in regulating metabolic enzymes and pathways. Neurodegenerative diseases, including Alzheimer’s and Parkinson’s, also show connections to dysregulated protein acetylation. In these conditions, altered acetylation can affect protein aggregation and neuronal function, contributing to disease pathology. Maintaining the proper balance of lysine acetylation is considered fundamental for cellular health and preventing a range of human diseases.