Dynamic interactions of Sup35p and PrP prion protein domains  modulate aggregate nucleation and seeding.
Prions are self-propagating infectious protein aggregates of mammals and fungi. The exact mechanism of prion formation is poorly understood. In a recent study, a comparative analysis of the aggregation propensities of chimeric proteins derived from the yeast Sup35p and mouse PrP prion proteins was performed in neuroblastoma cells. The cytosolic expression of the Sup35p domains NM, PrP and fusion proteins thereof revealed that the carboxyterminal domain of PrP (PrP90-230) mediated aggregate formation, while Sup35p N and M domains modulated aggregate size and frequency when fused to the globular domain of PrP. Here we further present co-aggregation studies of chimeric proteins with cytosolic PrP or a huntingtin fragment with an extended polyglutamine tract. Our studies demonstrate that cross-seeding by heterologous proteins requires sequence similarity with the aggregated protein domain. Taken together, these results demonstrate that nucleation and seeding of prion protein aggregates is strongly influenced by dynamic interactions between the aggregate core forming domain and its flanking regions.
Krammer
Carmen
C
Institute of Virology, Technische Universität München, Munich, Germany.
Kremmer
Elisabeth
E
Schätzl
Hermann M
HM
Vorberg
Ina
I
D000818:Animals; D045744:Cell Line, Tumor; D003600:Cytosol / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D010454:Peptide Termination Factors; D011328:Prions / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
D010454:Peptide Termination Factors; D011328:Prions; D011993:Recombinant Fusion Proteins; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins