N-terminal acetylation is a widespread chemical modification that occurs on proteins within cells. This process involves the addition of an acetyl group to the very first amino acid at the beginning of a protein chain, known as the N-terminus. Approximately 50-80% of eukaryotic proteins undergo this alteration. This modification changes the chemical properties of the protein’s N-terminus, often making it more hydrophobic.
The Process of N-Terminal Acetylation
The addition of an acetyl group to the N-terminus of a protein is carried out by N-terminal acetyltransferases (NATs). These enzymes transfer an acetyl group from acetyl-coenzyme A (Ac-CoA) to the alpha-amino group of the protein’s initial amino acid. This transfer neutralizes the positive charge of the N-terminal amino group.
Eight types of NATs have been identified in eukaryotes, designated NatA through NatH, each with specific preferences for which proteins they modify. Many NATs perform this modification as the protein is being synthesized on the ribosome. This is known as co-translational acetylation, where the NAT enzyme interacts with the ribosome to modify the nascent protein chain as it emerges.
Other NATs function post-translationally, meaning they modify proteins after their complete synthesis. The specific amino acid sequence at the N-terminus largely determines which NAT enzyme will modify a given protein.
Diverse Roles in Cellular Function
N-terminal acetylation influences a protein’s characteristics, impacting its function and ultimate fate within the cell. The acetyl group alters the N-terminal properties, which can affect how a protein folds, interacts with other molecules, and moves to specific cellular locations.
One role of N-terminal acetylation is in regulating protein stability and turnover. This modification can protect proteins from degradation by masking signals that would otherwise tag them for destruction by the cellular waste disposal system. For example, N-terminal acetylation of Cyclin B1 can shield its initial methionine residue, delaying its breakdown. Conversely, this modification can also mark specific proteins for degradation through a pathway involving ubiquitin ligases.
N-terminal acetylation also plays a part in directing proteins to their correct subcellular destinations. By altering the charge and hydrophobicity of the protein’s N-terminus, this modification can influence its interactions with cellular membranes or other targeting machinery. This helps ensure proteins arrive at the specific organelles or compartments where they are needed to perform their functions.
Furthermore, N-terminal acetylation can modulate protein-protein interactions. This modification can create new binding sites or change existing ones, affecting how proteins interact with their partners. For instance, N-terminal acetylation is important for the proper functioning of actin filaments, which are involved in cell shape and movement, by influencing how actin interacts with other proteins. This modification can also influence a protein’s overall activity by affecting its folding or conformational stability.
N-Terminal Acetylation and Health
Disruptions in N-terminal acetylation can have consequences for human health. Altered N-terminal acetylation has been associated with neurodegenerative diseases by affecting protein clearance mechanisms.
Specific neurodevelopmental disorders have been linked to problems with N-terminal acetylation. Mutations in genes like NAA10, a catalytic subunit of NatA, can lead to conditions characterized by developmental delays and intellectual disability. Similarly, imbalances in N-terminal acetylation have been implicated in the aggregation of proteins like FUS, which is observed in certain forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
N-terminal acetylation also plays a role in the progression of various cancers. NAT enzymes are known to regulate signal transduction pathways involved in cell growth, proliferation, and programmed cell death in different cancer types, including hepatocellular carcinoma, breast cancer, lung cancer, colorectal cancer, and prostate cancer. Targeting NAT-mediated acetylation holds potential as a strategy for inhibiting cancer progression.