Rosenblum J S, Gilula N B, Lerner R A
Department of Chemistry, Scripps Research Institute, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4471-3. doi: 10.1073/pnas.93.9.4471.
We report a previously unappreciated property of the signals that target organelle-specific proteins to their subcellular sites of action. Such targeting sequences are shown to be polymorphic. We discovered this polymorphism when we cloned the mitochondrial manganese-containing superoxide dismutase from cell lines of normal individuals and patients with genetic diseases of premature aging and compared their sequences to each other and to those previously reported. The polymorphism consists of a single nucleotide change in the region of the DNA that encodes the signal sequence such that either an alanine or valine is present. Subsequently, eight cell lines were analyzed and all three possible combinations of the two signal sequences were observed. Such signal sequence polymorphisms could result in diseases of distribution, where essential proteins are not properly targeted, thereby leading to absolute or relative deficiencies of critical enzymes within specific cellular compartments. Progeria and related syndromes may be diseases of distribution.
我们报告了一种以前未被认识到的信号特性，该信号将细胞器特异性蛋白质靶向其亚细胞作用位点。这种靶向序列显示出多态性。当我们从正常个体和早衰遗传病患者的细胞系中克隆含锰的线粒体超氧化物歧化酶，并将它们的序列相互比较以及与先前报道的序列进行比较时，我们发现了这种多态性。这种多态性由编码信号序列的DNA区域中的单个核苷酸变化组成，使得存在丙氨酸或缬氨酸。随后，对八个细胞系进行了分析，观察到了两种信号序列的所有三种可能组合。这种信号序列多态性可能导致分布性疾病，即必需蛋白质未被正确靶向，从而导致特定细胞区室内关键酶的绝对或相对缺乏。早衰症及相关综合征可能是分布性疾病。
