NR AWUT
AU Solforosi,L.; Bellon,A.; Schaller,M.; Cruite,J.T.; Abalos,G.C.; Williamson,R.A.
TI Toward molecular dissection of PrPc-PrPsc interactions
QU The Journal of Biological Chemistry 2007 Mar 9; 282(10): 7465-71
PT journal article; research support, n.i.h., extramural; research support, u.s. gov't, non-p.h.s.
AB Direct interaction between endogenous cellular prion protein (PrPc) and misfolded, disease-associated (PrPsc) conformers is a key event in prion propagation, which precedes templated conversion of PrPc into nascent PrPsc and prion infectivity. Although almost none of the molecular details of this pivotal process are understood, the persistence of individual prion strains suggests that assembly of the prion replicative complex is mechanistically precise. To systematically map defined regions of PrPc sequence that bind tightly to PrPsc, we have generated a comprehensive panel of over 45 motif-grafted antibodies containing overlapping peptide grafts collectively spanning PrP residues 19-231. Grafted antibody binding experiments, performed under stringent conditions, clearly identified only three distinct and independent high affinity PrPsc recognition motifs. The first of these binding motifs lies at the very N-terminal region of the mature PrP molecule within PrP-(23-33); the second motif lies within PrP-(98-110); and the third is contained within PrP-(136-158). Mutational analyses of these PrPsc-binding regions revealed that reactivity of the 23-33 and 98-110 segments are largely dependent upon the presence of multiple positively charged amino acid residues. These studies yield new insight into critical peptidic components composing one side of the prion replicative interface.
MH Binding Sites; Humans; Point Mutation; PrPc Proteins/*chemistry; PrPsc Proteins/*chemistry; Protein Conformation; Protein Interaction Mapping/*methods
AD Laura Solforosi (lsolf@scripps.edu), Anne Bellon (abellon@scripps.edu), Monica Schaller, Justin T. Cruite, Gil C. Abalos, R. Anthony Williamson (anthony@scripps.edu), Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA
SP englisch
PO USA
EA pdf-Datei und Supplement