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J Biol Chem February 7, 2003; 278 (6): 3726-34.
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Essential role of the prion protein N terminus in subcellular trafficking and half-life of cellular prion protein.

Nunziante M , Gilch S , Schätzl HM .

Aberrant metabolism and conformational alterations of the cellular prion protein (PrP(c)) are the underlying causes of transmissible spongiform encephalopathies in humans and animals. In cells, PrP(c) 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 PrP(c) 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 PrP(c). The same deletions caused a significant prolongation of cellular half-life of PrP(c) 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 PrP(c), 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.

PubMed ID: 12431994
Article link: J Biol Chem

Species referenced: Xenopus laevis
Genes referenced: c4bpa prnp