NR ARSW
AU Sarnataro,D.; Campana,V.; Paladino,S.; Stornaiuolo,M.; Nitsch,L.; Zurzolo,C.
TI PrPc association with lipid rafts in the early secretory pathway stabilizes its cellular conformation
QU Molecular Biology of the Cell 2004 Sep; 15(9): 4031-42
IA http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=515338
PT journal article
AB The pathological conversion of cellular prion protein (PrPc) into the scrapie prion protein (PrPsc) isoform appears to have a central role in the pathogenesis of transmissible spongiform encephalopathies. However, the identity of the intracellular compartment where this conversion occurs is unknown. Several lines of evidence indicate that detergent-resistant membrane domains (DRMs or rafts) could be involved in this process. We have characterized the association of PrPc to rafts during its biosynthesis. We found that PrPc associates with rafts already as an immature precursor in the endoplasmic reticulum. Interestingly, compared with the mature protein, the immature diglycosylated form has a different susceptibility to cholesterol depletion vs. sphingolipid depletion, suggesting that the two forms associate with different lipid domains. We also found that cholesterol depletion, which affects raft-association of the immature protein, slows down protein maturation and leads to protein misfolding. On the contrary, sphingolipid depletion does not have any effect on the kinetics of protein maturation or on the conformation of the protein. These data indicate that the early association of PrPc with cholesterol-enriched rafts facilitates its correct folding and reinforce the hypothesis that cholesterol and sphingolipids have different roles in PrP metabolism.
MH Animals; Cells, Cultured; Cholesterol/metabolism; Drug Stability; Endoplasmic Reticulum/metabolism; Membrane Microdomains/*metabolism; PrPc Proteins/*chemistry/*metabolism; Protein Conformation; Protein Folding; Protein Processing, Post-Translational; Rats; Research Support, Non-U.S. Gov't; Sphingolipids/metabolism; Subcellular Fractions/metabolism
AD Daniela Sarnataro, Vincenza Campana, Simona Paladino, Lucio Nitsch, Chiara Zurzolo (zurzolo@unina.it, zurzolo@pasteur.fr), Dipartimento di Biologia e Patologia Cellulare e Molecolare, Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, Universita degli Studi di Napoli Federico II, 80131 Napoli, Italy; Vincenza Campana, Simona Paladino, Chiara Zurzolo, Unité de Trafic Membranaire et Pathogénèse, Institut Pasteur, 75724 Paris Cedex 15, France; Mariano Stornaiuolo, Dipartimento di Biochimica e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, 80131 Napoli, Italy
SP englisch
PO USA