N-terminal methionine processing and N-alpha-acetylation are key determinants in intracellular protein sorting

  • Gabriella Forte

    Student thesis: Master of Philosophy


    N-terminal initiator methionine removal and N-alpha-acetylation represent two of the most common protein modification events in eukaryotes. N-terminal methionine removal occurs on two thirds of a given proteome and N-alpha-acetylation between 50-80% of cytosolic proteins. These modifications occur co-translationally as the nascent protein is being synthesised and therefore are amongst the earliest protein modification events. The primary determinant for these modifications is the N-terminal amino acid residue at position 2. Many secretory proteins are targeted via N-terminal signal sequences. Bioinformatics data has revealed that the signal sequences of secretory proteins have a strong observed bias against certain amino acids at position 2, specifically residues which are predicted to promote the most common N-terminal modifications (manuscript submitted Forte et al). In this study we focused upon secretory proteins which display this bias against N-terminal modification. It was found that mutation of these secretory signal sequences in a fashion that may promote N-terminal modification results in defective sorting of these proteins to the cytosol. This phenomenon was further investigated in vitro demonstrating the mis-sorted proteins are N-alpha-acetylated and in vivo showing that inhibition of N-alpha-acetylation rescued the defect. These findings indicate that N-alpha-acetylation can affect sorting of secretory proteins. Further bioinformatics data presented in this study show that proteins targeted to other subcellular locations via their N-termini may also exhibit a bias against N-terminal processing similar to signal sequences. Taken together these observations may indicate that N-terminal modification represents a novel sorting step in protein biogenesis.
    Date of Award31 Dec 2010
    Original languageEnglish
    Awarding Institution
    • The University of Manchester
    SupervisorColin Stirling (Supervisor)


    • methionine aminopeptidase
    • ER translocation
    • N-Acetylation

    Cite this