Post-Translational Modifications

Co-translational Post-Translational Modifications (PTMs)

Summary

Co-translational Post-Translational Modifications (PTMs) are chemical alterations enacted on a nascent polypeptide chain while it is still emerging from the ribosome. Unlike modifications that occur after release, these events are spatially and temporally coupled to translation, often coordinated by enzymes docked at the ribosomal exit tunnel or the ER translocon.

Key Points

  • 1Modifications occur while the polypeptide is still being synthesized by the ribosome
  • 2N-terminal Methionine Excision (NME) removes the initiator methionine
  • 3N-terminal Acetylation (NTA) neutralizes the N-terminal charge affecting stability
  • 4Signal peptide cleavage and N-linked glycosylation occur at the ER translocon
  • 5OST adds oligosaccharides to Asn-X-Ser/Thr motifs to recruit chaperones

Co-translational PTMs represent a critical layer of protein regulation that occurs before the polypeptide chain is fully synthesized. These modifications are essential for proper protein folding, stability, and function.

Cytosolic Mechanisms

N-terminal Methionine Excision (NME)

The initiator methionine is removed from the nascent chain by Methionine Aminopeptidases (MetAPs). This occurs when the second residue has a small, uncharged side chain (Ala, Cys, Gly, Pro, Ser, Thr, Val). NME exposes the true N-terminus, which can then undergo further modifications.

N-terminal Acetylation (NTA)

N-acetyltransferases (NATs) transfer an acetyl group from acetyl-CoA to the α-amino group of the N-terminus. This modification:

  • Neutralizes the positive charge at the N-terminus
  • Affects protein stability via the Ac/N-degron pathway
  • Influences protein-protein interactions
  • Is present on ~80% of human proteins

    • Secretory Pathway Modifications

    Signal Peptide Cleavage

    As the ribosome docks with the ER translocon, the Signal Peptidase Complex cleaves the hydrophobic signal sequence. This releases the mature N-terminus into the ER lumen.

    N-linked Glycosylation

    The Oligosaccharyltransferase (OST) complex adds a preassembled oligosaccharide (Glc₃Man₉GlcNAc₂) to asparagine residues in the consensus sequence Asn-X-Ser/Thr (where X ≠ Pro). This modification:

  • Aids in protein folding by recruiting ER chaperones (Calnexin, Calreticulin)
  • Serves as a quality control checkpoint
  • Occurs while the nascent chain is still emerging from the ribosome

    • Functional Significance

    Co-translational modifications are not merely decorative additions:

  • They restrict the conformational search space of the growing chain
  • They recruit chaperones to assist folding
  • They determine protein stability and half-life
  • They are essential for the proper function of secreted and membrane proteins

    • The coupling of these modifications to translation ensures that they occur at the earliest possible moment, before the polypeptide can misfold or aggregate.

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