Mechanism of Raft Action in Prion Conversion

It has been shown that direct cell-to-cell contact between infected cells and unin-fected cells (i.e., with PrPc and PrPSc being on opposite cell surfaces [71]), can efficiently induce the passage of prion infection between cells. The importance of this membrane environment in the conversion reaction has been underscored by

Biosynthese Von Prpsc

Fig. 10.1 Different models for the role of rafts in prion formation, based on the apparent implication of rafts in many features of prion protein trafficking. (A) Rafts may represent the vehicle of prion transport to the intracellular compartment (e.g., endoplasmic reticulum (ER), plasma membrane, endo-somes-lysosomes, caveolae) where the conformational changes could occur. (B) Rafts may embody the cofactors (protein-X or lipid chaperones) of the transconformation machinery. (C) Rafts may represent: (1) the membrane location where PrPc accumulates

Fig. 10.1 Different models for the role of rafts in prion formation, based on the apparent implication of rafts in many features of prion protein trafficking. (A) Rafts may represent the vehicle of prion transport to the intracellular compartment (e.g., endoplasmic reticulum (ER), plasma membrane, endo-somes-lysosomes, caveolae) where the conformational changes could occur. (B) Rafts may embody the cofactors (protein-X or lipid chaperones) of the transconformation machinery. (C) Rafts may represent: (1) the membrane location where PrPc accumulates and where it encounters PrPSc; thus, the prion conversion reaction would be enhanced in these microdomains. Alternatively (2), rafts may represent a membrane environment accumulating both PrPc and PrPSc; coalescence of these two specific prion rafts could favor and initiate prion conversion. (D) PrPc conformation could be favored and stabilized by association with specific raft domains, so that when PrPc exits them it is misfolded and might better interact with PrPSc and mediate transconformation.

several studies where specific lipids have been shown to play direct roles as chaperones in protein folding [72,73]. In particular, both PrPc and PrPSc can bind to raftlike membranes enriched in cholesterol and sphingolipids [74]. In order to analyze the role of lipid rafts in this conformational transition, binding of both the a-helical-enriched structure (a-PrP) and the b-sheet-enriched form (b-PrP) to model lipid membranes was recently investigated [75]. The result of these studies indicate that binding to raft membranes results in a stabilization of a-helical structures,

Prpc Synthesis Pathway

Fig. 10.2 Model for PrPc to PrPSc conversion in lipid rafts. PrPc associates with specific rafts early during its biosynthesis. Perturbation of this membrane environment promotes PrPc misfolding. Misfolded PrP, in the presence of PrPSc or of pathological mutants, can acquire the pathological conformation. Once formed, PrPSc can associate with new specific types of raft in which aggregation is favored.

Fig. 10.2 Model for PrPc to PrPSc conversion in lipid rafts. PrPc associates with specific rafts early during its biosynthesis. Perturbation of this membrane environment promotes PrPc misfolding. Misfolded PrP, in the presence of PrPSc or of pathological mutants, can acquire the pathological conformation. Once formed, PrPSc can associate with new specific types of raft in which aggregation is favored.

while interaction with negatively charged lipid (non-raft) membranes increases b-sheet content [74].

This evidence for a "protective role" of rafts in the transconformation process is further reinforced by the fact that, in a non-cellular assay, PrPc within isolated lipid rafts is highly resistant to conversion to PrPSc [32], and inhibition of sphingolipid synthesis in cells increases the rate of conversion of PrPc [76].

Our own data on the destabilization of PrPc folding in cholesterol depletion also support the hypothesis that the raft environment is necessary to stabilize the proper PrPc conformation, therefore suggesting that transconformation occurs outside of the rafts, where PrPc folding is destabilized and where misfolded PrP intermediates might be more prone to interact with PrPSc and to transconform (Fig. 10.2). However, the fact that recombinant b-PrP also has a high affinity for raft-like membranes [75] and that PrPSc is also found enriched in rafts [68] leads us to propose that, together with the protective role in prion transconformation, rafts could have a second role in promoting aggregation of PrPSc. In this scenario, PrPSc would form outside rafts in a non-protective environment but, once formed, PrPSc would be able to reassociate with the rafts (perhaps different to the rafts where PrPc is found), and this would favor its aggregation (Fig. 10.2).

This hypothesis is also supported by the data of Fantini et al. [77], who proposed that PrPc can maintain a non-pathological conformation by interacting with lipid rafts through a sphingolipid-binding domain (V3-like domain). Interestingly, in the E200K PrP mutant, which undergoes PrP transconformation in familial CJD, this mutation abrogates sphingomyelin recognition. A similar sphingolipid-bind-ing motif has also been identified in gp120 glycoprotein of HIV and in the b-amyloid peptide in Alzheimer's disease, suggesting a role of lipid rafts in the pathogenesis of these different diseases.

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