NR AFXK
AU Jackson,G.S.; Murray,I.; Hosszu,L.L.P.; Gibbs,N.; Waltho,J.P.; Clarke,A.R.; Collinge,J.
TI Location and properties of metal-binding sites on the human prion protein
QU Proceedings of the National Academy of Sciences of the United States of America 2001 Jul 17; 98(15): 8531-5
PT journal article
AB Although a functional role in copper binding has been suggested for the prion protein, evidence for binding at affinities characteristic of authentic metal-binding proteins has been lacking. By presentation of copper(II) ions in the presence of the weak chelator glycine, we have now characterized two high-affinity binding sites for divalent transition metals within the human prion protein. One is in the N-terminal octapeptide-repeat segment and has a K(d) for copper(II) of 10(-14) M, with other metals (Ni(2+), Zn(2+), and Mn(2+)) binding three or more orders of magnitude more weakly. However, NMR and fluorescence data reveal a previously unreported second site around histidines 96 and 111, a region of the molecule known to be crucial for prion propagation. The K(d) for copper(II) at this site is 4 x 10(-14) M, whereas nickel(II), zinc(II), and manganese(II) bind 6, 7, and 10 orders of magnitude more weakly, respectively, regardless of whether the protein is in its oxidized alpha-helical (alpha-PrP) or reduced beta-sheet (beta-PrP) conformation. A role for prion protein (PrP) in copper metabolism or transport seems likely and disturbance of this function may be involved in prion-related neurotoxicity.
MH Amino Acid Sequence; Binding Sites; Cations, Divalent/chemistry; Copper/chemistry; Glycine/chemistry; Human; Manganese/chemistry; Metals/*chemistry; Molecular Sequence Data; Nickel/chemistry; Prions/*chemistry; Support, Non-U.S. Gov't; Zinc/chemistry
AD Medical Research Council Prion Unit, Department of Neurogenetics, Imperial College School of Medicine at St. Mary's, London W2 1NY, United Kingdom.
SP englisch
PO USA