NR AQLK
AU Kiachopoulos,S.; Heske,J.; Tatzelt,J.; Winklhofer,K.F.
TI Misfolding of the prion protein at the plasma membrane induces endocytosis, intracellular retention and degradation
QU Traffic (Copenhagen, Denmark) 2004 Jun; 5(6): 426-36
PT journal article
AB Suramin induces misfolding of the cellular prion protein (PrPc) and interferes with the propagation of infectious scrapie prions. A mechanistic analysis of this effect revealed that suramin-induced misfolding occurs at the plasma membrane and is dependent on the proximal region of the C-terminal domain (aa 90-158) of PrPc. The conformational transition induces rapid internalization, mediated by the unstructured N-terminal domain, and subsequent intracellular degradation of PrPc. As a consequence, PrP Delta N adopts a misfolded conformation at the plasma membrane; however, internalization is significantly delayed. We also found that misfolding and intracellular retention of PrPc can be induced by copper and that, moreover, copper interferes with the propagation of the pathogenic prion protein (PrPsc) in scrapie-infected N2a cells. Our study revealed a quality control pathway for aberrant PrP conformers present at the plasma membrane and identified distinct PrP domains involved.
MH Animals; Blotting, Western; Cell Line, Transformed; Cell Membrane/*metabolism; Copper/pharmacology; *Endocytosis; Fluorescent Antibody Technique, Indirect; Microscopy, Fluorescence; PrPc Proteins/chemistry/drug effects/*metabolism; PrPsc Proteins/drug effects/metabolism; Precipitin Tests; Prions/*metabolism; Protein Conformation; *Protein Folding; Protein Structure, Tertiary; Protein Transport; Rats; Research Support, Non-U.S. Gov't; Suramin/pharmacology
AD Department of Cellular Biochemistry, Max-Planck-Institut für Biochemie, Am Klopferspitz 18, D-82152 Martinsried, Germany.
SP englisch
PO Dänemark