Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, 185 Meeting Street, Post Office Box G-L2, Providence, RI 02912, USA.
Science. 2010 Oct 29;330(6004):680-3. doi: 10.1126/science.1197785.
According to the prion hypothesis, atypical phenotypes arise when a prion protein adopts an alternative conformation and persist when that form assembles into self-replicating aggregates. Amyloid formation in vitro provides a model for this protein-misfolding pathway, but the mechanism by which this process interacts with the cellular environment to produce transmissible phenotypes is poorly understood. Using the yeast prion Sup35/[PSI(+)], we found that protein conformation determined the size distribution of aggregates through its interactions with a molecular chaperone. Shifts in this range created variations in aggregate abundance among cells because of a size threshold for transmission, and this heterogeneity, along with aggregate growth and fragmentation, induced age-dependent fluctuations in phenotype. Thus, prion conformations may specify phenotypes as population averages in a dynamic system.
根据朊病毒假说，当朊病毒蛋白采用另一种构象时，就会出现非典型表型，并且当这种形式组装成自我复制的聚集体时，这种表型就会持续存在。体外淀粉样蛋白的形成为这种蛋白质错误折叠途径提供了模型，但尚不清楚这个过程如何与细胞环境相互作用产生可传播的表型。利用酵母朊病毒 Sup35/[PSI(+)], 我们发现蛋白质构象通过与分子伴侣相互作用决定了聚集体的大小分布。由于存在一个可传播的大小阈值，该范围的变化导致了细胞之间聚集体丰度的变化，这种异质性，以及聚集体的生长和碎片化，诱导了表型随年龄的波动。因此，朊病毒构象可能会在动态系统中指定表型作为群体平均值。
