DePace A H, Santoso A, Hillner P, Weissman J S
Department of Cellular and Molecular Pharmacology, University of California-San Francisco, 94143-0450, USA.
Cell. 1998 Jun 26;93(7):1241-52. doi: 10.1016/s0092-8674(00)81467-1.
The yeast [PSI+] factor propagates by a prion-like mechanism involving self-replicating Sup35p amyloids. We identified multiple Sup35p mutants that either are poorly recruited into, or cause curing of, wildtype amyloids in vivo. In vitro, these mutants showed markedly decreased rates of amyloid formation, strongly supporting the protein-only prion hypothesis. Kinetic analysis suggests that the prion state replicates by accelerating slow conformational changes rather than by providing stable nuclei. Strikingly, our mutations map exclusively within a short glutamine/asparagine-rich region of Sup35p, and all but one occur at polar residues. Even after replacement of this region with polyglutamine, Sup35p retains its ability to form amyloids. These and other considerations suggest similarities between the prion-like propagation of [PSI+] and polyglutamine-mediated pathogenesis of several neurodegenerative diseases.
酵母[PSI+]因子通过一种涉及自我复制的Sup35p淀粉样蛋白的类朊病毒机制进行传播。我们鉴定出多个Sup35p突变体，它们在体内要么很难被募集到野生型淀粉样蛋白中，要么导致野生型淀粉样蛋白的消除。在体外，这些突变体显示出淀粉样蛋白形成速率显著降低，这有力地支持了仅蛋白质的朊病毒假说。动力学分析表明，朊病毒状态通过加速缓慢的构象变化而非提供稳定的核来进行复制。引人注目的是，我们的突变仅定位在Sup35p一个富含谷氨酰胺/天冬酰胺的短区域内，并且除一个突变外，所有突变都发生在极性残基处。即使将该区域替换为聚谷氨酰胺后，Sup35p仍保留其形成淀粉样蛋白的能力。这些以及其他因素表明，[PSI+]的类朊病毒传播与几种神经退行性疾病的聚谷氨酰胺介导的发病机制之间存在相似性。
