Strain conformation, primary structure and the propagation of the yeast prion [PSI(+)]

Prion proteins can adopt multiple different infectious strain conformations. Here we examine how the sequence of a prion protein affects its capacity to propagate specific conformations by exploiting our ability to create two distinct infectious conformations of the yeast [PSI(+)] prion protein Sup35p, termed Sc4 and Sc37. PNM2, a Sup35p (G58D) point mutant originally identified for its dominant interference with prion propagation, leads to rapid, recessive loss of Sc4 but does not interfere with Sc37 propagation. PNM2 destabilizes the amyloid core of Sc37 causing compensatory effects that slow prion growth but aid prion division and result in robust Sc37 propagation. In contrast, PNM2 does not affect the structure or chaperone-mediated division of Sc4, but interferes with its delivery to daughter cells. Thus, effective delivery of infectious particles during cell division is a critical and conformation-dependent step in prion inheritance.