All cyclophilins and FK506 binding proteins are, individually and collectively, dispensable for viability in Saccharomyces cerevisiae
All cyclophilins and FK506 binding proteins are, individually and collectively, dispensable for viability in Saccharomyces cerevisiae
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DOI：
10.1073/pnas.94.24.13093
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发表时间：
1997-11-25
影响因子：
11.1
通讯作者：
Heitman, J
中科院分区：
文献类型：
--
作者：
Dolinski, K;Muir, S;Heitman, J
亲环蛋白和 FK506 结合蛋白 (FKBP) 与环孢菌素 A、FK506 和雷帕霉素结合并介导它们的免疫抑制和毒性作用，但这些蛋白的生理功能很大程度上未知。亲环蛋白和 FKBP 是普遍存在且高度保守的酶，可催化肽基-脯氨酰异构化，这是体外蛋白质折叠过程中的限速步骤。我们通过酿酒酵母中的遗传方法解决了它们的功能。先前在酵母中鉴定出五种亲环蛋白和三种 FKBP。我们还鉴定了另外四种酶：Cpr6 和 Cpr7，它们是哺乳动物亲环蛋白 40 的同源物，最近也被其他人独立分离；Cpr8，分泌途径亲环蛋白 Cpr4 的同源物；以及 Fpr4，核仁 FKBP Fpr3 的同源物。八种亲环蛋白或四种 FKBP 都不是必需的。令人惊讶的是，缺乏所有 12 种亲免蛋白的酵母突变体都是可行的，并且十二联体突变体的表型是通过简单添加每个单独突变的微妙表型而产生的。我们得出的结论是，亲环蛋白和 FKBP 在蛋白质折叠中并不发挥重要的一般作用，并且几乎没有发现不同酶之间功能重叠的证据。我们提出，每种亲环蛋白和 FKBP 都调节有限数量的独特伴侣蛋白，这些蛋白仍有待鉴定。
The cyclophilins and FK506 binding proteins (FKBPs) bind to cyclosporin A, FK506, and rapamycin and mediate their immunosuppressive and toxic effects, but the physiological functions of these proteins are largely unknown. Cyclophilins and FKBPs are ubiquitous and highly conserved enzymes that catalyze peptidyl-prolyl isomerization, a rate-limiting step during in vitro protein folding. We have addressed their functions by a genetic approach in the yeast Saccharomyces cerevisiae. Five cyclophilins and three FKBPs previously were identified in yeast. We identified four additional enzymes: Cpr6 and Cpr7, which are homologs of mammalian cyclophilin 40 that have also recently been independently isolated by others, Cpr8, a homolog of the secretory pathway cyclophilin Cpr4, and Fpr4, a homolog of the nucleolar FKBP, Fpr3. None of the eight cyclophilins or four FKBPs were essential. Surprisingly, yeast mutants lacking all 12 immunophilins were viable, and the phenotype of the dodecuplet mutant resulted from simple addition of the subtle phenotypes of each individual mutation. We conclude that cyclophilins and FKBPs do not play an essential general role in protein folding and find little evidence of functional overlap between the different enzymes. We propose that each cyclophilin and FKBP instead regulates a restricted number of unique partner proteins that remain to be identified.