Probing the mysteries of prion folding

PHYS 185

Susan Lindquist, lindquist_admin@wi.mit.edu, Howard Hughes Medical Institute, Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142
Misfolded proteins are usually degraded by the cell. However some persist in their altered shapes. In mammalian prion diseases, misfolded forms convert other proteins to the same deadly forms and are transmitted between organisms. In yeast, however, prions are not deleterious, but can provide a remarkable mechanism for the inheritance of protein-based phenotypes. For Sup35, a yeast prion involved in translation termination, conversion to the prion state involves the formation of an amyloid fold by one of its protein domains through an unusual molten oligomeric intermediate. We have used a variety of chemical probes to investigate the nature of this intermediate. We have also developed a peptide array technology to identify the critical nucleating contacts involved in the conversion of Sup35. Using these arrays, we determined that this region also controls two previously mysterious properties of prion biology: the species barrier and the formation of distinct prion strains.