Document Detail


Conversion of raft associated prion protein to the protease-resistant state requires insertion of PrP-res (PrP(Sc)) into contiguous membranes.
MedLine Citation:
PMID:  11867531     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Prion protein (PrP) is usually attached to membranes by a glycosylphosphatidylinositol-anchor that associates with detergent-resistant membranes (DRMs), or rafts. To model the molecular processes that might occur during the initial infection of cells with exogenous transmissible spongiform encephalopathy (TSE) agents, we examined the effect of membrane association on the conversion of the normal protease-sensitive PrP isoform (PrP-sen) to the protease-resistant isoform (PrP-res). A cell-free conversion reaction approximating physiological conditions was used, which contained purified DRMs as a source of PrP-sen and brain microsomes from scrapie-infected mice as a source of PrP-res. Interestingly, DRM-associated PrP-sen was not converted to PrP-res until the PrP-sen was either released from DRMs by treatment with phosphatidylinositol-specific phospholipase C (PI-PLC), or the combined membrane fractions were treated with the membrane-fusing agent polyethylene glycol (PEG). PEG-assisted conversion was optimal at pH 6--7, and acid pre-treating the DRMs was not sufficient to permit conversion without PI-PLC or PEG, arguing against late endosomes/lysosomes as primary compartments for PrP conversion. These observations raise the possibility that generation of new PrP-res during TSE infection requires (i) removal of PrP-sen from target cells; (ii) an exchange of membranes between cells; or (iii) insertion of incoming PrP-res into the raft domains of recipient cells.
Authors:
Gerald S Baron; Kathy Wehrly; David W Dorward; Bruce Chesebro; Byron Caughey
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The EMBO journal     Volume:  21     ISSN:  0261-4189     ISO Abbreviation:  EMBO J.     Publication Date:  2002 Mar 
Date Detail:
Created Date:  2002-02-27     Completed Date:  2002-05-14     Revised Date:  2013-04-18    
Medline Journal Info:
Nlm Unique ID:  8208664     Medline TA:  EMBO J     Country:  England    
Other Details:
Languages:  eng     Pagination:  1031-40     Citation Subset:  IM    
Affiliation:
Laboratory of Persistent Viral Diseases, NIAID, NIH, Rocky Mountain Laboratories, 903 South 4th Street, Hamilton, MT 59840, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Membrane / metabolism*
Cell-Free System
Drug Resistance
Endopeptidases / pharmacology*
Glycosylphosphatidylinositols / metabolism*
Hydrogen-Ion Concentration
Membrane Fusion / drug effects
Membrane Microdomains / metabolism*
Mice
Microsomes / metabolism
Neuroblastoma / pathology
Phosphatidylinositol Diacylglycerol-Lyase
Phosphoinositide Phospholipase C
Polyethylene Glycols / pharmacology
PrPSc Proteins / drug effects,  metabolism*
Protein Isoforms / metabolism*
Recombinant Fusion Proteins / metabolism
Scrapie / metabolism
Tumor Cells, Cultured
Type C Phospholipases / pharmacology
Chemical
Reg. No./Substance:
0/Glycosylphosphatidylinositols; 0/Polyethylene Glycols; 0/PrPSc Proteins; 0/Protein Isoforms; 0/Recombinant Fusion Proteins; EC 3.1.4.-/Type C Phospholipases; EC 3.1.4.11/Phosphoinositide Phospholipase C; EC 3.4.-/Endopeptidases; EC 4.6.1.13/Phosphatidylinositol Diacylglycerol-Lyase
Comments/Corrections

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