Dynamics and reversibility of protein N-terminal acetylation

The life of a human cell is controlled by proteins. Different chemical groups may be coupled to proteins, and thereby function as tags controlling protein function. A chemical moiety, acetyl, is coupled to nearly every single protein in human cells. Our research group at UiB has defined the entire machinery in human cells attaching this tag to the end (N-terminal end) of proteins. However, we do not yet entirely understand why all proteins are acetylated, but researchers have the last couple of years shown that the acetyl-tags may control the stability and trafficking of proteins. In any case, it is becoming clear that the acetylation of proteins is a process of crucial importance for humans. Recently, a lethal syndrome affecting infant males, was found to be caused by a mutation in an enzyme responsible for N-terminal acetylation (NAT-enzyme). It was also shown that NAT enzymes may play a role in the development and progression of cancers. Further, hunger and pain are also controlled by these acetyl moieties. So far, it has not been proven that these acetyl groups may be actively removed from proteins, but we recently discovered that certain proteins display an altered N-terminal acetylation status depending on the metabolic state of the cell. Further, we recently discovered a novel enzyme modifying one of the most important proteins of the cell and thereby controlling cell motility.

Acetylation is a very common protein modification occurring both at lysine residues within proteins (lysine acetylation) and at N-termini of proteins (N-terminal acetylation). The metabolic hub molecule Acetyl-CoA acts as the acetyl donor in both reaction s. Lysine acetylation has been studied extensively and it provides important regulatory control of histones and transcription factors due to the reversibility of the reaction mediated by the action of lysine acetyltransferases (KATs) versus the lysine dea cetylases (KDACs). Furthermore, metabolic regulation of lysine acetylation is mediated via alterations of Acetyl-CoA levels. The functional importance of N-terminal acetylation has recently gained significant interest and involvement in protein degradat ion, protein complex formation and inhibition of endoplasmic reticulum translocation has been demonstrated. Our recent studies revealed that a majority of soluble eukaryotic proteins were N-terminally acetylated. N-terminal acetylation is catalyzed by N-terminal acetyltransferases (NATs). During the last decade, the applicant and coworkers discovered and characterized the presumed complete human NAT-machinery. However, in contrast to lysine acetylation, N-terminal acetylation is considered irreversible . In order to proceed beyond state-of-the-art within this field, I would like to investigate the potential novel concepts of dynamics and reversibility of N-terminal acetylation, including the identification of N-terminal deacetylases (objectives above) . Given the links between NATs/N-terminal acetylation and disease, this investigation is likely to be relevant within the fields of biology and medicine, including principles of protein/peptide regulation, as well as cancer development and progression. With the extensive relevant experience of the applicant and a state-of-the-art collaborative team, a favourable degree of feasibility can be anticipated for this high risk/high gain project.