Cell Biology and Metabolism Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
J Cell Biol. 2010 Feb 22;188(4):515-26. doi: 10.1083/jcb.200911115. Epub 2010 Feb 15.
Protein translocation into the endoplasmic reticulum is mediated by signal sequences that vary widely in primary structure. In vitro studies suggest that such signal sequence variations may correspond to subtly different functional properties. Whether comparable functional differences exist in vivo and are of sufficient magnitude to impact organism physiology is unknown. Here, we investigate this issue by analyzing in transgenic mice the impact of signal sequence efficiency for mammalian prion protein (PrP). We find that replacement of the average efficiency signal sequence of PrP with more efficient signals rescues mice from neurodegeneration caused by otherwise pathogenic PrP mutants in a downstream hydrophobic domain (HD). This effect is explained by the demonstration that efficient signal sequence function precludes generation of a cytosolically exposed, disease-causing transmembrane form of PrP mediated by the HD mutants. Thus, signal sequences are functionally nonequivalent in vivo, with intrinsic inefficiency of the native PrP signal being required for pathogenesis of a subset of disease-causing PrP mutations.
蛋白质向内质网的易位是由信号序列介导的，这些信号序列在一级结构上差异很大。体外研究表明，这种信号序列的变化可能对应于略微不同的功能特性。在体内是否存在类似的功能差异，以及这些差异是否足以影响生物体的生理机能尚不清楚。在这里，我们通过分析转基因小鼠来研究这个问题，研究了信号序列对哺乳动物朊病毒蛋白（PrP）效率的影响。我们发现，用更有效的信号序列替换 PrP 的平均效率信号序列，可以挽救因下游疏水区（HD）中其他致病性 PrP 突变而导致的神经退行性变。这一效应可以通过证明有效的信号序列功能排除了由 HD 突变体介导的细胞质暴露、引起疾病的跨膜形式的 PrP 的产生来解释。因此，信号序列在体内的功能是不等效的，天然 PrP 信号的固有低效性是引起一部分致病性 PrP 突变的发病机制所必需的。
