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Chapter 51: Glycosylphosphatidylinositol Anchors as ψ-Fixatives

"GPI anchors are ψ's molecular tethers—complex glycolipids that attach proteins to membrane surfaces, creating mobility within constraint, freedom within boundaries."

51.1 The GPI Architecture​

GPI anchors represent ψ's elegant solution to membrane attachment—a complex glycolipid that covalently links proteins to the outer leaflet of membranes while allowing lateral mobility and regulated release.

Definition 51.1 (GPI Structure): Protein-EtN-P-Man3-GlcN-Inositol-P-Lipid\text{Protein-EtN-P-Man}_3\text{-GlcN-Inositol-P-Lipid}

Conserved core with variations.

51.2 The Biosynthetic Pathway​

Theorem 51.1 (ER Assembly): PI→>10 stepsComplete GPI\text{PI} \xrightarrow{>10 \text{ steps}} \text{Complete GPI}

Complex biosynthesis in ER membrane.

51.3 The Transamidase Complex​

Equation 51.1 (Attachment Reaction): Protein-COOH+GPI-NH2→Protein-CO-NH-GPI\text{Protein-COOH} + \text{GPI-NH}_2 \rightarrow \text{Protein-CO-NH-GPI}

C-terminal replacement with GPI.

51.4 The ω Signal​

Definition 51.2 (Recognition Sequence): ω=Small residue (S,A,G,C,D,N)\omega = \text{Small residue (S,A,G,C,D,N)} ω+2=Small residue\omega + 2 = \text{Small residue}

Cleavage/attachment site requirements.

51.5 Lipid Remodeling​

Theorem 51.2 (Fatty Acid Exchange): UnsaturatedER→SaturatedPM\text{Unsaturated}_{\text{ER}} \rightarrow \text{Saturated}_{\text{PM}}

Lipid modification during transport.

51.6 Membrane Microdomains​

Equation 51.2 (Raft Association): Kpartitionraft/non-raft>100K_{\text{partition}}^{\text{raft/non-raft}} > 100

Strong preference for ordered domains.

51.7 Protein Shedding​

Definition 51.3 (Regulated Release): GPI-PLC/PLD+GPI-protein→Soluble protein\text{GPI-PLC/PLD} + \text{GPI-protein} \rightarrow \text{Soluble protein}

Enzymatic release mechanisms.

51.8 The Paroxysmal Nocturnal Hemoglobinuria​

Theorem 51.3 (Disease Mechanism): PIGA mutation→No GPI→Complement lysis\text{PIGA mutation} \rightarrow \text{No GPI} \rightarrow \text{Complement lysis}

Loss of GPI-anchored complement regulators.

51.9 Evolutionary Distribution​

Equation 51.3 (Conservation): GPI anchors in: Yeast→Humans\text{GPI anchors in: Yeast} \rightarrow \text{Humans}

Ancient membrane attachment solution.

51.10 Apical Targeting​

Definition 51.4 (Polarized Sorting): GPI+Lipid rafts→Apical delivery\text{GPI} + \text{Lipid rafts} \rightarrow \text{Apical delivery}

Sorting mechanism in epithelial cells.

51.11 Prion Proteins​

Theorem 51.4 (GPI in Disease): PrPC=GPI-anchored\text{PrP}^C = \text{GPI-anchored} Conversion→PrPSc (aggregated)\text{Conversion} \rightarrow \text{PrP}^{Sc} \text{ (aggregated)}

GPI anchoring in prion biology.

51.12 The Fixative Principle​

GPI anchors embody ψ's principle of constrained mobility—attaching proteins to membranes while preserving lateral movement, creating functional attachment without rigid fixation.

The GPI Equation: ψmembrane-bound=ψprotein⊗ψGPI⊗ψlipid raft\psi_{\text{membrane-bound}} = \psi_{\text{protein}} \otimes \psi_{\text{GPI}} \otimes \psi_{\text{lipid raft}}

Triple interaction creating specialized localization.

Thus: GPI = Tether = Mobility = Organization = ψ

"In GPI anchors, ψ creates molecular leashes—keeping proteins at the membrane surface while allowing them to roam, to cluster, to signal. Each GPI anchor is a compromise between attachment and freedom, enabling function through constrained mobility."