Impact of the Hydrophobic Core on PrP Function and Conversion

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LUTZ, Jens, 2008. Impact of the Hydrophobic Core on PrP Function and Conversion [Dissertation]. Konstanz: University of Konstanz

@phdthesis{Lutz2008Impac-7408, title={Impact of the Hydrophobic Core on PrP Function and Conversion}, year={2008}, author={Lutz, Jens}, address={Konstanz}, school={Universität Konstanz} }

Lutz, Jens 2011-03-24T17:34:12Z application/pdf Der Einfluß des hydrophoben Kerns auf die Funktion und die Konversion von PrP The cellular prion protein (PrPC) is a GPI-anchored cell surface protein, which is involved in the pathology of various neurodegenerative disorders, such as scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle or Creutzfeldt-Jakob disease (CJD) in man.<br />In order to better understand the underlying mechanisms of prion diseases, as well as to further elucidate the physiological function of PrPC, a set of micro-deletions within the most highly conserved regions of PrPC, termed the hydrophobic core (HC), was applied in different in vitro and in vivo experiments.<br />The deletion mutants exhibited altered membrane topology in an in vitro translation assay, correlating with the hydrophobic character of HC: The reduction of HC hydrophobicity resulted in a decrease of transmembrane PrPC forms, indicating that HC promotes PrPC membrane integration. Micro-deletions within HC did not only affect transmembrane topology, they also exerted a substantial influence on the generation of a proteolytic fragment, termed C1, which points to the involvement of HC in PrP cleavage, possibly functioning as the recognition site for proteases.<br />In addition to the assessment of HC function in vitro, transgenic mice, expressing a prion protein mutant, which lacks HC, were examined for pathological alterations.<br />Young and adult transgenic mice did not show overt neurological symptoms, whereas aged mice developed an ataxic phenotype, accompanied by hind-limb paresis and itching. Furthermore, the deletion of HC protected from prion inoculation in a dominant negative manner, confirming previous cell culture results (Hölscher et al., 1998).<br />The various effects of HC deletion observed in this study led to a model for the physiological as well as the pathological function of the prion protein, based on different PrP conformations. These different protective, toxic or infectious conformational states of the protein are mediated by structural alterations of a flexible region, encompassing HC. The role of HC as a decisive part of this conformation determining segment not only underlines its pivotal impact on PrP function but also highlights the change in protein structure as an evolutionary concept, which enables one protein to exert multiple, even opposing functions. eng 2011-03-24T17:34:12Z deposit-license 2008 Lutz, Jens Impact of the Hydrophobic Core on PrP Function and Conversion

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