| First Author | Lutz J | Year | 2010 |
| Journal | Biochem Biophys Res Commun | Volume | 393 |
| Issue | 3 | Pages | 439-44 |
| PubMed ID | 20138835 | Mgi Jnum | J:158829 |
| Mgi Id | MGI:4440694 | Doi | 10.1016/j.bbrc.2010.02.015 |
| Citation | Lutz J, et al. (2010) Microdeletions within the hydrophobic core region of cellular prion protein alter its topology and metabolism. Biochem Biophys Res Commun 393(3):439-44 |
| abstractText | The cellular prion protein (PrP(C)) is a GPI-anchored cell-surface protein. A small subset of PrP(C) molecules, however, can be integrated into the ER-membrane via a transmembrane domain (TM), which also harbors the most highly conserved regions of PrP(C), termed the hydrophobic core (HC). A mutation in HC is associated with prion disease resulting in an enhanced formation of a transmembrane form ((Ctm)PrP), which has thus been postulated to be a neurotoxic molecule besides PrP(Sc). To elucidate a possible physiological function of the transmembrane domain, we created a set of mutants carrying microdeletions of 2-8 aminoacids within HC between position 114 and 121. Here, we show that these mutations display reduced propensity for transmembrane topology. In addition, the mutants exhibited alterations in the formation of the C1 proteolytic fragment, which is generated by alpha-cleavage during normal PrP(C) metabolism, indicating that HC might function as recognition site for the protease(s) responsible for PrP(C) alpha-cleavage. Interestingly, the mutant G113V, corresponding to a hereditary form of prion disease in humans, displayed increased (Ctm)PrP topology and decreased alpha-cleavage in our in vitro assay. In conclusion, HC represents an essential determinant for transmembrane PrP topology, whereas the high evolutionary conservation of this region is rather based upon preservation of PrP(C) alpha-cleavage, thus highlighting the biological importance of this cleavage. |
