Protein N-terminal acetylation - From molecular mechanisms to human disease
Prof. Thomas Arnesen | University of Bergen, Norway

Protein N-terminal acetylation is among the most common types of protein modifications occurring on approximately 50 % of all soluble yeast proteins and more than 80 % of all soluble 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. 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. The importance of N-terminal acetylation in human cell biology and disease has been increasingly recognized.
The human NatA complex 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 hNatA complex results from recent findings demonstrating correlation between expression of the hNatA subunits and tumour development. Functional studies of hNatA 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, hNatA may be a potential target for cancer therapy.
Selected references
  • Aksnes H, Drazic A, Marie M, Arnesen T (2016) First Things First: Vital Protein Marks by N-Terminal Acetyltransferases. Trends Biochem Sci 41(9):746-60.
  • Linster E, Stephan I, Bienvenut WV, Maple-Grødem J, Myklebust LM, Huber M, Reichelt M, Sticht C, Geir Møller S, Meinnel T, Arnesen T, Giglione C, Hell R, Wirtz M (2015) Downregulation of N-terminal acetylation triggers ABA-mediated drought responses in Arabidopsis. Nature Commun 6:7640.
  • Myklebust LM, Van Damme P, Støve SI, Dörfel MJ, Abboud A, Kalvik TV, Grauffel C, Jonckheere V, Wu Y, Swensen J, Kaasa H, Liszczak G, Marmorstein R, Reuter N, Lyon GJ, Gevaert K, Arnesen T (2015) Biochemical and cellular analysis of Ogden syndrome reveals downstream Nt-acetylation defects. Hum Mol Genet 24(7):1956-76.
  • Liszczak G, Goldberg JM, Foyn H, Petersson EJ, Arnesen T, Marmorstein R (2013) Molecular basis for N-terminal acetylation by the heterodimeric NatA complex. Nature Struct Mol Biol 20(9):1098-105.
  • Arnesen T (2011) Towards a functional understanding of protein N-terminal acetylation. PLoS Biology 9(5):e1001074.
  • Van Damme P, Hole K, Pimenta-Marques A, Helsens K, Vandekerckhove J, Martinho RG, Gevaert K, Arnesen T (2011) NatF Contributes to an Evolutionary Shift in Protein N-Terminal Acetylation and Is Important for Normal Chromosome Segregation. PLoS Genet 7(7):e1002169.