The cellular isoform of prion protein, PrPc, is a GPI-anchored glycoprotein residing on the outer face of the plasma membrane of neurones and several other cell types. Its gene (Prnp) has been highly conserved during vertebrate evolution. While the crucial role of PrPc in the replication of prions and the pathogenesis of transmissible spongiform encephalopathies has been recognised several years ago, its normal biological function has largely remained elusive. In this sub-project, the focus is on the TM1 domain of PrPc (codons 110-135) one of the most highly conserved regions, thus strongly suggesting an essential role in the execution of the physiological function of this protein. Benefiting from the strong partnership and close, interdisciplinary co-operation within the consortium, the structure and function of the murine PrPc TM1 domain shall comprehensively be studied (A) in vitro, (B) at the cellular level and (C) in vivo (transgenic mice), respectively, drawing on an existing set of deletions mutants centred on codons 114-121. Additional mutants shall be included that have been reported to favour a stable ctm conformation of the PrPc molecule (i.e. a specific transmembrane conformation associated with a genetic form of human prion disease), whereas the wild-type protein is found to adopt such conformation less frequently.