The non-prion SUP35 preexists in large chaperone-containing molecular complexes.

Prions, misfolded proteins that aggregate, cause an array of progressively deteriorating conditions to which, currently, there are no effective treatments. The presently accepted model indicates that the soluble non-prion forms of prion-forming proteins, such as the well-studied SUP35, do not exist in large aggregated molecular complexes. Here, we show using analytical ultracentrifugation with fluorescent detection that the non-prion form of SUP35 exists in a range of discretely sized soluble complexes (19S, 28S, 39S, 57S, and 70S-200S). Similar to the [PSI+] aggregated complexes, each of these [psi-] complexes associates at stoichiometric levels with a large variety of molecular chaperones: HSP70 proteins comprise the major component. Another yeast prion-forming protein, RNQ1 (known to promote the production of the prion SUP35 state), is also present in SUP35 complexes. These results establish that the non-prion SUP35, like its prion form, is predisposed to form large molecular complexes containing chaperones and other prion-forming proteins. These results agree with our previous studies on the huntingtin protein. That the normal forms for aggregation-prone proteins may preexist in large molecular complexes has important ramifications for the progression of diseases involving protein aggregation.