Translational Protein Research

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Protein N-terminal acetylation

Protein N-terminal acetylation is among the most common types of protein modifications occurring on approximately 50 % of all yeast proteins and more than 80 % of all human proteins. Surprisingly, there is yet no clear functional understanding of how N-terminal acetylation affects proteins in general, although recent data indicate roles in protein degradation and targeting. N-terminal acetylation is a co-translational process occurring on the ribosomes and is considered irreversible. An N-terminal acetyltransferase (NAT) transfers an Acetyl group from Acetyl Coenzyme A to the alpha-amino group of the N-terminal amino acid residue of the protein. 
During the last six years, the human NATs have been identified and characterized by our group. In humans as in yeast, three NAT complexes NatA, NatB and NatC are believed to perform most N-terminal acetylations. Each NAT complex is composed of specific subunits and acetylates a specific subset of substrates. Very recently, also human NatD, NatE and NatF were identified. A number of studies have described various aspects of N-terminal acetylation in humans, such as substrates, NAT knockdown phenotypes, and expression patterns of NAT subunits. Through these studies, a complex and specific system of N-terminal acetylation has been revealed. The importance of N-terminal acetylation in human cell biology and disease is increasingly recognized.

NatA and cancer

The human NatA complex, composed of the catalytic subunit NAA10 (ARD1) and the auxiliary subunit NAA15 (NATH), is the major N-terminal acetyltransferase in humans cotranslationally acetylating nascent polypeptides with Ala-, Ser-, Thr-, Val- or Gly- N-termini after cleavage of the initiator Met.
An increasing interest to the NatA complex results from recent findings demonstrating correlation between expression of the hNatA subunits and tumour development. NAA15 overexpression was found characteristic for gastric cancer, thyroid neoplasms, and neuroblastomas, while upregulation of NAA10 was found in hepatocellular carcinoma, colon cancer, and breast cancer. Several studies indicate on drop in NAA10/NAA15 expression levels during differentiation. Functional studies of NatA revealed that its subunits are essential for the maintenance of growth and survival of several cancer cell types, and knockdown of NatA sensitized cancer cells to drug treatment. Taken together, NatA may be a potential target for cancer therapy.