NR AQYU
AU Lysek,D.A.; Wüthrich,K.
TI Prion protein interaction with the C-terminal SH3 domain of Grb2 studied using NMR and optical spectroscopy
QU Biochemistry 2004 Aug 17; 43(32): 10393-9
PT journal article
AB Transmissible spongiform encephalopathies have been observed exclusively in organisms expressing the host-encoded prion protein (PrP). The function of the cellular isoform of PrP found in healthy organisms has so far not been identified, although there are indications of a role in signal transduction in neurons. To gain further insight into the functional properties of cellular PrP, this paper investigated the binding of the C-terminal SH3 domain of the murine growth factor receptor-bound protein 2 (Grb2) to the murine PrP, using NMR, fluorescence, and circular dichroism spectroscopy. The SH3-binding site in murine PrP was thus found to be in the highly conserved region of residues 100-109, which contains prolines in positions 101 and 104. The protein-protein interaction, with a K(D) value of 5.5 microM, is abolished when either of these two prolines is replaced by leucine. In humans, two corresponding Pro --> Leu exchanges are found in patients who present with the Gerstmann-Sträussler-Scheinker syndrome. The results of the present study thus indicate a possible mechanism by which amino acid exchanges could influence a specific protein-protein interaction in a complex signal transduction cascade, which might be of functional significance in health and disease.
MH Amino Acid Substitution/*genetics; Animals; Binding Sites; Comparative Study; Conserved Sequence; Magnetic Resonance Spectroscopy; Mice; Models, Molecular; PrPc Proteins/genetics/*metabolism; Protein Binding; Protein Structure, Tertiary; Proteins/*metabolism; Support, Non-U.S. Gov't; *src Homology Domains
AD Institut für Molekularbiologie und Biophysik, Eidgenössische Technische Hochschule Zürich, CH-8093 Zürich, Switzerland.
SP englisch
PO USA