Post-Translational Modifications

Post-Translational Modifications

Summary

Post-translational modifications are covalent alterations to proteins following biosynthesis, exponentially expanding the proteome's functional diversity. Key modifications include phosphorylation, glycosylation, ubiquitination, and lipidation.

Key Points

  • 1>200 different PTM types dramatically expand proteome diversity
  • 2Phosphorylation is the key regulatory switch in signaling
  • 3Glycosylation critical for folding and quality control
  • 4Ubiquitination controls protein degradation

Post-translational modifications (PTMs) transform the ~20,000 protein-coding genes into millions of functionally distinct protein species.

Expanding the Proteome

The genome encodes only 20 standard amino acids, but PTMs vastly expand functional diversity:

- >200 different PTM types have been identified

  • Many proteins carry multiple modifications
  • PTMs can be reversible (regulatory) or permanent (structural)

    • Major PTM Categories

    Phosphorylation

    The most studied regulatory modification:

  • Addition of phosphate (PO₄³⁻) to Ser, Thr, or Tyr

    • - Catalyzed by kinases; removed by phosphatases

  • Introduces negative charge and steric bulk
  • Regulates activity, localization, and interactions
  • Central to signal transduction
  • ~30% of proteins are phosphorylated

    • Glycosylation

    Addition of carbohydrate chains:

    N-linked glycosylation

  • Attached to Asn in Asn-X-Ser/Thr motifs
  • Occurs in the ER lumen
  • Critical for protein folding and quality control

    • O-linked glycosylation

  • Attached to Ser/Thr
  • Occurs mainly in the Golgi
  • Important for mucins and cell surface proteins

    • Ubiquitination

    Attachment of ubiquitin protein:

    - Monoubiquitination: Endocytosis, DNA repair

    - K48-polyubiquitination: Targets for proteasomal degradation

    - K63-polyubiquitination: Signaling, autophagy

  • E1 → E2 → E3 enzymatic cascade

    • Lipidation

    Attachment of lipid groups:

    - Myristoylation: 14-carbon fatty acid

    - Palmitoylation: 16-carbon fatty acid (reversible)

    - Prenylation: Isoprenoid groups

  • Anchors proteins to membranes

    • Other Important PTMs

    - Acetylation: Neutralizes positive charge of Lys

    - Methylation: Lys, Arg (especially on histones)

    - SUMOylation: SUMO protein attachment

    - ADP-ribosylation: Regulatory modification

    Functional Consequences

    PTMs alter protein properties:

    - Charge: Phosphorylation, acetylation

    - Hydrophobicity: Lipidation

    - Steric bulk: Glycosylation, ubiquitination

    - Conformation: Can induce structural changes

    - Stability: Ubiquitination targets for degradation

    - Localization: Lipidation anchors to membranes

    - Interactions: Create or disrupt binding sites

    PTMs and Disease

    Dysregulation of PTMs underlies many diseases:

    - Cancer: Aberrant kinase signaling

    - Diabetes: Insulin signaling defects

    - Neurodegeneration: Tau hyperphosphorylation, protein aggregation

    - Congenital disorders: Glycosylation defects

    Previous
    Non-Ribosomal Peptide Synthesis (NRPS)
    Next
    Intrinsically Disordered Proteins (IDPs)