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Characterization of the unfolded state of the human prion protein

NMR analysis shows that the unfolded state has three stretches of residual beta-sheet character. In addition, several hydrophobic clusters can be identified. Most strikingly, the introduction of the native disulfide bridge considerably rigidifies the entire protein. This phenomenon is linked to fibril formation properties of the prion protein. The polypeptide chain forms fibrils only its oxidized state, in the absence of the SS-bridge, no fibers are formed. The location of the native disulfide moreover correlates with a hotspot of inherited human prion disease-related mutations. 17 out of 25 disease-related mutations are found within this region of the polypeptide chain. Therefore, the Schwalbe group proposed that differences in the conformational dynamics around the disulfide bridge, brought about by inherited mutations, in the unfolded state modulate the tendency of the human prion protein to form fibrils.

The results were published on 30 October 2009 in the journal Angewandte Chemie (International Edition) [Link]



Full Reference: Gerum C, Silvers R, Wirmer-Bartoschek J, Schwalbe H. 2009. Unfolded-State Structure and Dynamics Influence the Fibril Formation of Human Prion Protein. Angew Chem Int Ed. [Epub ahead of print on 30 Oct 2009].