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
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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.
- Initiation on the cytoplasmic side of the ER:
-
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.
-
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.