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J. Biol. Chem., Vol. 278, Issue 6, 3726-3734, February 7, 2003
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From the Gene Center Munich, Max von Pettenkofer Institute for
Virology, Faculty of Medicine, Ludwig-Maximilians-University,
Feodor-Lynen-Strasse 25, D-81377 Munich, Germany
Aberrant metabolism and conformational
alterations of the cellular prion protein (PrPc) are
the underlying causes of transmissible spongiform encephalopathies in
humans and animals. In cells, PrPc is modified
post-translationally and transported along the secretory pathway to the
plasma membrane, where it is attached to the cell surface by a
glycosylphosphatidylinositol anchor. In surface biotinylation assays we
observed that deletions within the unstructured N terminus of murine
PrPc led to a significant reduction of internalization of
PrP after transfection of murine neuroblastoma cells. Truncation of the entire N terminus most significantly inhibited internalization of
PrPc. The same deletions caused a significant prolongation
of cellular half-life of PrPc and a delay in the transport
through the secretory pathway to the cell surface. There was no
difference in the glycosylation kinetics, indicating that all PrP
constructs equally passed endoplasmic reticulum-based cellular quality
control. Addition of the N terminus of the Xenopus
laevis PrP, which does not encode a copper-binding repeat
element, to N-terminally truncated mouse PrP restored the wild type
phenotype. These results provide deeper insight into the life cycle of
the PrPc, raising the novel possibility of a targeting
function of its N-proximal part by interacting with the secretory and
the endocytic machinery. They also indicate the conservation of this
targeting property in evolution.
Essential Role of the Prion Protein N Terminus in Subcellular
Trafficking and Half-life of Cellular Prion Protein*
*
This work was supported in part by Deutsche
Forschungsgemeinschaft Grant SCHA 594/3-3, Sonder Forschungsbereich
596, and by European Union BIOMED Program Contract
BMH4-CT98-6040).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Virology, Max
von Pettenkofer Institute, Gene Center Munich, Feodor-Lynen-Str. 25, Munich D-81377, Germany. Tel.: 49-89-2180-6855; Fax:
49-89-2180-6898; E-mail: schaetzl@lmb.uni-muenchen.de.
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