Lecture Notes

Introduction to Glycosylation Disorders

• Glycosylation is a critical post-translational modification affecting protein stability, localization, and function.
• Disorders of glycosylation have been increasingly recognized with advancements in next-generation sequencing (NGS).
• Among glycosylation pathways, the GPI anchor and glycosphingolipid (GSL) pathways play essential roles in cellular physiology and pathology.
• Importance for pediatric neurologists:
  • These pathways have significant implications in neurodevelopmental disorders, epilepsy, and systemic anomalies.
  • Understanding these disorders aids in accurate diagnosis and personalized management.

  GPI Anchors: Role and Biosynthesis

  Role of GPI Anchors

  • GPI anchors are glycolipid structures that tether proteins to the cell membrane.
  • Functions:
    • Facilitate protein sorting into specialized lipid domains (lipid rafts).
    • Involved in signaling, immune response, and enzymatic activity.
    • Critical for neural development and synaptic functioning.

    Stages of GPI Anchor Biosynthesis

    1. Stage 1: Synthesis of GPI Precursors (Endoplasmic Reticulum)

       • Initiation on the cytoplasmic side of the ER:
         • UDP-GlcNAc is transferred to phosphatidylinositol (PI) by PIGA.
         • Enzymatic complex includes PIGC, PIGH, PIGP, PIGQ, PIGY, DPM2.
       • De-N-acetylation of GlcNAc-PI by PIGL, forming GlcN-PI.
       • Translocation to the ER lumen:
         • Mediated by flipping of the GlcN-PI molecule.
       • Modification:
         • Acylation of the inositol ring by PIGW.
         • Addition of three mannose residues by PIGM, PIGX, and PIGV.
         • Incorporation of ethanolamine phosphate groups by PIGN, PIGB, PIGO, PIGF, and PIGG.

    2. Stage 2: GPI Anchor Attachment to Proteins

       • Occurs in the ER lumen.
       • Transamidase complex (PIGT, PIGK, PIGS, PIGU, GPAA1):
         • Recognizes GPI-anchor signal sequences on proteins.
         • Facilitates the transfer of the GPI anchor to proteins and cleaves the C-terminal signal peptide.

    3. Stage 3: Remodeling of the GPI Anchor

       • Essential for the functional integration of GPI-anchored proteins (GPI-APs) into lipid rafts.
       • Modifications:
         • Deacylation of inositol by PGAP1.
         • Removal of ethanolamine-phosphate by PGAP5.
         • Exchange of unsaturated fatty acid for a saturated fatty acid at the sn-2 position by PGAP2 and PGAP3.
       • Importance:
         • Optimizes the protein’s localization and signaling properties.

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