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Misfolding of the Prion Protein at the Plasma Membrane Induces Endocytosis, Intracellular Retention and Degradation
Author(s) -
Kiachopoulos Sophia,
Heske Johanna,
Tatzelt Jörg,
Winklhofer Konstanze F.
Publication year - 2004
Publication title -
traffic
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.677
H-Index - 130
eISSN - 1600-0854
pISSN - 1398-9219
DOI - 10.1111/j.1398-9219.2004.00185.x
Subject(s) - internalization , intracellular , endocytosis , microbiology and biotechnology , endosome , biology , scrapie , protein folding , membrane , biophysics , biochemistry , prion protein , receptor , medicine , disease , pathology
Suramin induces misfolding of the cellular prion protein (PrP C ) 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 PrP C . The conformational transition induces rapid internalization, mediated by the unstructured N‐ terminal domain, and subsequent intracellular degradation of PrP C . As a consequence, PrPΔN adopts a misfolded conformation at the plasma membrane; however, internalization is significantly delayed. We also found that misfolding and intracellular retention of PrP C can be induced by copper and that, moreover, copper interferes with the propagation of the pathogenic prion protein (PrP Sc ) 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.