NR AOWC
AU Lysek,D.A.; Wüthrich,K.
TI Characterisation of the interaction between the C-terminal SH3 domain of murine Grb2 and the murine prion protein
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Poster session - BR-11
PT Konferenz-Poster
AB
Transmissible spongiform encephalopathies (TSE) are a group of infectious neuronal disorders, such as scrapie in sheep, bovine spongiform encephalopathy (BSE), chronic wasting disease (CWD) in cervids, and Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker syndrome (GSS) in man.
A major component identified so far in tissue specimen with TSE infectivity is an aggregated form of the host-encoded prion protein (PrP). The function of the cellular isoform of the prion protein (PrPc) found in healthy organisms has stayed an enigma, although several reports have been published that relate PrPc function to signal transduction in neurons. Here, the binding of the C-terminal SH3 domain of murine Grb2 to the murine prion protein, which has previously been identified through a yeast-two-hybrid screen, has been monitored by various spectroscopic methods, including NMR, fluorescence, and circular diachroism. The SH3-binding site on the prion protein has been mapped to a highly conserved region, consisting of residues 101-110 (numbering of hPrP). Tight binding between the two partners, with KD = 5.5 uM, as evidenced by fluorescence spectroscopy, can be explained by the occurrence of prolines at positions 102 and 105 in PrP, as well as by the complimentary charge distribution on the two protein surfaces. Furthermore, this protein-protein interaction is significantly weakened, when either of the two GSS syndrome-related mutations, P102L or P105L, is introduced into the murine prion protein, indicating a possible mechanism by which these two mutations could contribute to increased susceptibility to GSS syndrome.
AD Dominikus A. Lysek, Kurt Wüthrich, Institute for Molecular Biology and Biophysiks, Swiss Federal Institute of Technology Zürich (ETH), Switzerland
SP englisch
PO Deutschland