All aspects of the life of a human cell are controlled by proteins. Proteins can be modified by different chemical groups functioning as tags controlling protein function. One particular chemical group, acetyl, is coupled to nearly every single protein in our 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. The enzymes doing this job are called NAT-enzymes. Surprisingly, we do not yet understand why most proteins are acetylated, but in recent years researchers have 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. For instance, such acetyl tagging or lack thereof may impact cancer development or cause heart disease. In this project we will investigate how the NAT-enzymes may compete with enzymes putting other tags on proteins. We believe that different tags may differently steer the fate of proteins and that this balance must be maintained to prevent disease.
Protein modifications are at the heart of biological regulation and a majority of human proteins undergo some kind of chemical modification that may regulate protein functionality. At some hotspots like the protein N-terminus there may be competition between different modifications and this N-terminal code may have a decisive impact on protein fate and downstream signalling. N-terminal acetylation (Nt-Ac) is the most abundant of these modifications and is catalysed by N-terminal acetyltransferases (NATs). NAA10 and NAA15, which together constitute the NatA complex, the major NAT in humans, are implicated in cancer and congenital disorders including congenital heart disease (CHD). NatA co-translationally acetylates protein N-termini. Additionally, there is a cellular population of NAA10, the catalytic subunit, which is not bound to the NatA complex. How these two NatA subunits cause or contribute to disease progression is not understood. Interestingly however, the types of pathology connected to malfunctioning of NatA versus NAA10 suggest highly distinct biochemical roles for the NatA complex versus the NAA10 monomer. Recently, several subjects from a cohort of CHD cases were found to harbour pathogenic NAA15 variants in a way that impaired NatA function. In cancer, data suggest that NAA10 is a pro-proliferative and pro-survival protein as a part of the NatA complex with NAA15, while monomeric NAA10 is anti-metastatic. NterCode will explore novel concepts of protein regulation to study the mechanisms linking NAA10 and NAA10-NAA15 (NatA) activity to cancer phenotypes and heart disease. To this end, NterCode will utilize unique cell models that will distinguish contributions from NAA10 and the NatA complex.