Structural insights into a yeast prion illuminate nucleation and strain diversity.
Self-perpetuating changes in the conformations of amyloidogenic proteins play vital roles in normal biology and disease. Despite intense research, the architecture and conformational conversion of amyloids remain poorly understood. Amyloid conformers of Sup35 are the molecular embodiment of the yeast prion known as [PSI], which produces heritable changes in phenotype through self-perpetuating changes in protein folding. Here we determine the nature of Sup35's cooperatively folded amyloid core, and use this information to investigate central questions in prion biology. Specific segments of the amyloid core form intermolecular contacts in a 'Head-to-Head', 'Tail-to-Tail' fashion, but the 'Central Core' is sequestered through intramolecular contacts. The Head acquires productive interactions first, and these nucleate assembly. Variations in the length of the amyloid core and the nature of intermolecular interfaces form the structural basis of distinct prion 'strains', which produce variant phenotypes in vivo. These findings resolve several problems in yeast prion biology and have broad implications for other amyloids.
Krishnan
Rajaraman
R
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.
Lindquist
Susan L
SL
D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D003545:Cysteine / Q000235:genetics / Q000378:metabolism; D014644:Genetic Variation / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010454:Peptide Termination Factors; D010641:Phenotype; D011328:Prions / Q000737:chemistry* / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000737:chemistry* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000682:Amyloid; D010454:Peptide Termination Factors; D011328:Prions; D021122:Protein Subunits; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D003545:Cysteine