| Summary: | <p>Abstract</p> <p>Background</p> <p>It has been reported that cellular prion protein (PrP<sup>c</sup>) co-localizes with caveolin-1 and participates to signal transduction events by recruiting Fyn kinase. As PrP<sup>c</sup> is a secreted protein anchored to the outer surface membrane through a glycosylphosphatidylinositol (GPI) anchor (<sup>sec</sup>PrP) and caveolin-1 is located in the inner leaflet of plasma membrane, there is a problem of how the two proteins can physically interact each other and transduce signals.</p> <p>Results</p> <p>By using the GST-fusion proteins system we observed that PrP<sup>c</sup> strongly interacts with caveolin-1 scaffolding domain and with a caveolin-1 hydrophilic C-terminal region, but not with the caveolin-1 N-terminal region. In vitro binding experiments were also performed to define the site(s) of PrP<sup>c</sup> interacting with cav-1. The results are consistent with a participation of PrP<sup>c</sup> octapeptide repeats motif in the binding to caveolin-1 scaffolding domain. The caveolar localization of PrP<sup>c</sup> was ascertained by co-immunoprecipitation, by co-localization after flotation in density gradients and by confocal microscopy analysis of PrP<sup>c</sup> and caveolin-1 distributions in a neuronal cell line (GN11) expressing caveolin-1 at high levels.</p> <p>Conclusions</p> <p>We observed that, after antibody-mediated cross-linking or copper treatment, PrP<sup>c</sup> was internalized probably into caveolae. We propose that following translocation from rafts to caveolae or caveolae-like domains, <sup>sec</sup>PrP could interact with caveolin-1 and induce signal transduction events.</p>
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