PDF(Pubmed)
Abstract：
Prion variants are self-perpetuating conformers of a single protein that assemble into amyloid fibers and confer unique phenotypic states. Multiple prion variants can arise, particularly in response to changing environments, and interact within an organism. These interactions are often competitive, with one variant establishing phenotypic dominance over the others. This dominance has been linked to the competition for non-prion state protein, which must be converted to the prion state via a nucleated polymerization mechanism. However, the intrinsic rates of conversion, determined by the conformation of the variant, cannot explain prion variant dominance, suggesting a more complex interaction. Using the yeast prion system [PSI+ ], we have determined the mechanism of dominance of the [PSI+ ]Strong variant over the [PSI+ ]Weak variant in vivo. When mixed by mating, phenotypic dominance is established in zygotes, but the two variants persist and co-exist in the lineage descended from this cell. [PSI+ ]Strong propagons, the heritable unit, are amplified at the expense of [PSI+ ]Weak propagons, through the efficient conversion of soluble Sup35 protein, as revealed by fluorescence photobleaching experiments employing variant-specific mutants of Sup35. This competition, however, is highly sensitive to the fragmentation of [PSI+ ]Strong amyloid fibers, with even transient inhibition of the fragmentation catalyst Hsp104 promoting amplification of [PSI+ ]Weak propagons. Reducing the number of [PSI+ ]Strong propagons prior to mating, similarly promotes [PSI+ ]Weak amplification and conversion of soluble Sup35, indicating that template number and conversion efficiency combine to determine dominance. Thus, prion variant dominance is not an absolute hierarchy but rather an outcome arising from the dynamic interplay between unique protein conformations and their interactions with distinct cellular proteostatic niches.
摘要：
朊病毒变体是组装成淀粉样蛋白纤维并赋予独特表型状态的单一蛋白质的自我延续构象异构体。可能会出现多种朊病毒变体，特别是为了应对不断变化的环境，并在生物体内相互作用。这些互动往往是竞争性的，一个变体建立表型优势。这种优势与非朊病毒状态蛋白的竞争有关，必须通过成核聚合机制转化为朊病毒状态。然而,内在转换率，由变体的构象决定，无法解释朊病毒变异优势，暗示了更复杂的互动。使用酵母朊病毒系统[PSI+]，我们已经确定了体内[PSI]强变体相对于[PSI]弱变体的优势机制。当通过交配混合时，表型优势在受精卵中建立，但这两种变异在这个细胞后代的谱系中持续存在并共存。[PSI+]强传播，可遗传单位，以[PSI+]弱传播为代价进行放大，通过可溶性Sup35蛋白的有效转化，如使用Sup35的变体特异性突变体的荧光光漂白实验所揭示的。这场比赛,然而,对[PSI+]强淀粉样蛋白纤维的碎片高度敏感，甚至瞬时抑制碎裂催化剂Hsp104，促进[PSI]弱传播子的放大。在交配前减少[PSI+]强传播体的数量，类似地促进可溶性Sup35的[PSI]弱扩增和转化，表明模板数和转化效率结合确定优势。因此，pr病毒变体优势不是绝对的层次结构，而是由于独特的蛋白质构象及其与不同的细胞蛋白抑制壁ni之间的相互作用之间的动态相互作用而产生的结果。
