Chien Peter, DePace Angela H, Collins Sean R, Weissman Jonathan S
Graduate Group in Biophysics, University of California-San Francisco, San Francisco, California 94143-2240, USA.
Nature. 2003 Aug 21;424(6951):948-51. doi: 10.1038/nature01894.
Self-propagating beta-sheet-rich protein aggregates are implicated in a wide range of protein-misfolding phenomena, including amyloid diseases and prion-based inheritance. Two properties have emerged as common features of amyloids. Amyloid formation is ubiquitous: many unrelated proteins form such aggregates and even a single polypeptide can misfold into multiple forms--a process that is thought to underlie prion strain variation. Despite this promiscuity, amyloid propagation can be highly sequence specific: amyloid fibres often fail to catalyse the aggregation of other amyloidogenic proteins. In prions, this specificity leads to barriers that limit transmission between species. Using the yeast prion [PSI+], we show in vitro that point mutations in Sup35p, the protein determinant of [PSI+], alter the range of 'infectious' conformations, which in turn changes amyloid seeding specificity. We generate a new transmission barrier in vivo by using these mutations to specifically disfavour subsets of prion strains. The ability of mutations to alter the conformations of amyloid states without preventing amyloid formation altogether provides a general mechanism for the generation of prion transmission barriers and may help to explain how mutations alter toxicity in conformational diseases.
富含β-折叠的自传播蛋白聚集体与多种蛋白质错误折叠现象有关，包括淀粉样疾病和基于朊病毒的遗传。两种特性已成为淀粉样蛋白的共同特征。淀粉样蛋白的形成无处不在：许多不相关的蛋白质都会形成这样的聚集体，甚至单个多肽也会错误折叠成多种形式——这一过程被认为是朊病毒株变异的基础。尽管存在这种随意性，但淀粉样蛋白的传播可能具有高度的序列特异性：淀粉样纤维通常无法催化其他淀粉样蛋白生成蛋白的聚集。在朊病毒中，这种特异性会导致限制物种间传播的屏障。利用酵母朊病毒[PSI+]，我们在体外表明，[PSI+]的蛋白质决定因子Sup35p中的点突变会改变“传染性”构象的范围，进而改变淀粉样蛋白的种子特异性。我们通过使用这些突变来特别不利于朊病毒株的子集，在体内产生了一种新的传播屏障。突变能够改变淀粉样状态的构象而不完全阻止淀粉样蛋白的形成，这为产生朊病毒传播屏障提供了一种普遍机制，可能有助于解释突变如何改变构象疾病中的毒性。
